Faculty Bibliography

INTRODUCTION/BACKGROUND:This study investigates whether midlife cortisol levels predict Alzheimer's disease (AD) biomarker burden 15 years later, with particular attention to sex differences and menopausal status. METHODS:F]Flortaucipir) positron emission tomography (PET) imaging conducted 15 years later. We performed multivariable regression analyses adjusted for confounders including, apolipoprotein E4 (APOE4) status. RESULTS:Elevated midlife cortisol correlated with increased amyloid deposition, specifically in post-menopausal women, predominantly in posterior cingulate, precuneus, and frontal-lateral regions (p < 0.05). No significant associations were observed with tau burden or in males. DISCUSSION/CONCLUSIONS:These findings reveal post-menopausal women with high midlife cortisol are at increased risk of AD. Results highlight the importance of identifying early risk factors when biomarkers are detectable but cognitive impairment is absent. HIGHLIGHTS/CONCLUSIONS:High midlife cortisol is linked to increased amyloid deposition in post-menopausal women. Cortisol showed no association with tau pathology. Post-menopausal hormone changes may amplify cortisol's effects on amyloid.

BACKGROUND:In Down syndrome (DS) and Alzheimer's disease (AD), nerve growth factor precursor protein (proNGF) accumulates in the brain. However, its non-invasive detection using neuron-derived extracellular vesicles (NDEVs) from plasma remains unexplored. METHODS:We included 139 adults with DS (45 asymptomatic [aDS], 94 symptomatic for AD [sDS]) and 37 healthy controls. NDEVs were isolated from plasma. ProNGF and tetraspanin (CD81) were quantified by enzyme-linked immunosorbent assay. We assessed proNGF/CD81 changes with age, along the AD continuum (aDS and sDS), and associations with cerebrospinal fluid (CSF), plasma biomarkers, episodic memory, and basal forebrain volume. RESULTS:In DS, proNGF/CD81 levels increased with age and were higher in NDEVs from asymptomatic and symptomatic individuals compared to controls, with the highest levels in the symptomatic group. ProNGF correlated with CSF phosphorylated tau (p-tau)181, plasma p-tau217, neurofilament light chain, and episodic memory. DISCUSSION/CONCLUSIONS:ProNGF/CD81 levels in NDEVs increase along the AD continuum in DS and parallel tau pathology, indicating the potential as a promising biomarker for monitoring disease progression in plasma. HIGHLIGHTS/CONCLUSIONS:Nerve growth factor precursor protein (ProNGF)/tetraspanin (CD81) ratio increased in the third decade of life, 20 years before Alzheimer's disease (AD) symptom onset in Down syndrome (DS). proNGF/CD81 concentrations were significantly higher in individuals with DS compared to controls and were notably elevated in individuals with DS and symptomatic AD compared to asymptomatic AD. proNGF/CD81 concentrations were associated with tau pathology and neuronal injury.

We here present evidence-based guidelines for the pharmacological treatment of migraine. These guidelines, created by the Italian Society for the Study of Headache and the International Headache Society, aim to offer clear, actionable recommendations to healthcare professionals. They incorporate evidence-based recommendations from randomized controlled trials and expert-based opinions. The guidelines follow the GRADE approach for assessing the quality of evidence. The guideline development involved a systematic review of literature across multiple databases, adherence to Cochrane review methods, and a structured framework for data extraction and interpretation. Although the guidelines provide a robust foundation for migraine treatment, they also highlight gaps in current research, such as the paucity of head-to-head drug comparisons and the need for long-term outcome studies. These guidelines serve as a resource to standardize migraine treatment and promote high-quality care across different healthcare settings.

The mechanisms behind comorbid symptoms of depression in persons with epilepsy (PWE) remain largely unknown. Our study aimed to learn whether seizures moderate fluctuations in depressive symptoms in PWE when controlling for preictal symptoms of depression. We enrolled 57 adult PWE admitted to the New York University (NYU) Langone Epilepsy Monitoring Unit (EMU) from 2021 to 2024. Thirty-seven participants had a seizure. Twenty of the admitted patients did not have seizures during the admission period and therefore served as controls. All participants were seizure free for > 7 days prior to participation. Upon admission, all participants completed the Montgomery-Asberg Depression Rating Scale (MADRS) to evaluate baseline mood. The MADRS was repeated acutely (4-24 h post seizure or admission) and subacutely (2-7 days post seizure or discharge) for both groups. Linear regression models revealed that individuals with higher baseline MADRS scores (indicating higher depressive symptoms) experienced worse mood acutely post-seizure, while lower baseline MADRS scores were associated with acute mood improvement (R² = 0.59, p < 0.001). Experiencing a seizure was not associated with subacute mood outcomes, which were instead driven by acute mood state (R² = 0.56, p < 0.001). In conclusion, we found that seizures exacerbate pre-ictal depressive symptoms and that post-ictal depressive symptoms persist up to 7 days after seizure resolution. This study may provide evidence for a bidirectional relationship and demonstrate a vicious cycle between depression and epilepsy.

Spetzler-Martin Grade IV arteriovenous malformations (AVMs) are challenging due to high risks associated with both treatment and natural progression. This study compares the outcomes of microsurgical resection and stereotactic radiosurgery (SRS) in high-grade AVMs, analyzing obliteration rates, complications, and functional outcomes. A retrospective cohort of 96 patients treated with either microsurgical resection (33 patients) or SRS (63 patients) was analyzed. Propensity-score matching was employed to account for baseline variables such as AVM size (cm), preoperative embolization and rupture status. Primary endpoints included AVM obliteration, complication rates, and modified Rankin Scale (mRS) scores. After matching, 31 patients per group were analyzed. Microsurgical resection achieved significantly higher obliteration rates (87.1%) compared to SRS (32.3%, p < 0.001). In the matched SRS cohort (n = 31), the actuarial obliteration rates were 11% (95% CI: 0-22%) at 1 year, 17% (95% CI: 0-31%) at 3 years, and 43% (95% CI: 13-63%) at 5 years post-treatment. Complication rates were similar (32.3% resection, 38.7% SRS, p = 0.6). Functional outcomes in terms of improvement in modified Rankin Scale (mRS) scores were observed in 50.0% of microsurgery patients and 41.4% of SRS patients. However, the absolute number of patients improving was similar (13 vs. 12), and the microsurgery group had more cases of worsening mRS scores compared to the SRS group (4 vs. 2). The difference was not statistically significant (p = 0.4). Microsurgical resection offers superior obliteration rates for high-grade AVMs with comparable complication risks to SRS. SRS remains a valuable alternative for select patients, particularly those ineligible for resection. Future research should focus on optimizing multimodal treatment approaches. Clinical trial number Not applicable.

RGS8-associated paraneoplastic neurologic syndrome (PNS) is a recently-described disorder associated with lymphomas and typically presenting with severe, rapidly-progressing cerebellar dysfunction. We describe a patient who presented with mild signs of cerebellar dysfunction, including ocular motor abnormalities and impaired tandem gait. CSF showed elevated protein and a neural-restricted antibody pattern. Mesenteric lymphadenopathy on abdominal CT was biopsied and diagnosed as follicular B-cell lymphoma. After four years, the previously-detected antibody pattern was identified as RGS8 antibodies. This case describes the first RGS8-PNS patient presenting with a subtle and ocular motor predominant cerebellar syndrome with low-grade lymphoma.

BACKGROUND:Flow-diverter stents (FDS) have become the standard of care for a wide range of intracranial aneurysms, but their efficacy/safety in the context of recurrent/recanalized aneurysms following stent-assisted coiling (SAC) is not well established. We evaluate the outcomes of FDS retreatment in a large multicenter cohort. METHODS:We retrospectively analyzed data from 118 patients across 22 institutions who underwent FDS retreatment for recurrent/persistent aneurysms after SAC (2008-22). The primary outcome was angiographic occlusion status at last follow-up, categorized as complete (100%), near-complete (90-99%), or incomplete (<90%) occlusion. Secondary outcomes included procedural complications and clinical outcomes measured by the modified Rankin Scale (mRS). RESULTS:A total of 118 patients (median age 57, 74.6% female) with median follow-up of 15.3 months were identified. Complete occlusion was achieved in 62.5% and near-complete occlusion in 25%. FDS deployment within the pre-existing stent was successful in 98.3% of cases. Major complications occurred in 3.4% of cases, including postoperative aneurysmal rupture with resultant mortality (1.6%) and thromboembolic events with long-term disability (1.6%). Favorable clinical outcomes (mRS 0-2) were observed in 95.1% of patients. Wider aneurysm neck diameter was a significant predictor of incomplete occlusion (adjusted OR (aOR) 1.23 per mm, P=0.044), with male sex trending towards association with non-occlusion (aOR 3.2, P=0.07), while baseline hypertension was associated with complete occlusion (aOR 0.32, P=0.048). CONCLUSIONS:FDS treatment for recurrent/residual aneurysms after SAC represents a viable treatment option for these challenging cases with acceptable safety and reasonable occlusion rates, although lower than de novo FDS occlusion rates.

Astrocytes are a highly abundant glial cell type and perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogeneous subtypes. The subtype identity and functions are, at least in part, associated with their anatomical location and can be highly restricted to strategically important anatomical domains. Here, we report that astrocytes forming the glia limitans superficialis, the outermost border of the brain and spinal cord, are a highly specialized astrocyte subtype and can be identified by a single marker: myocilin (Myoc). We show that glia limitans superficialis astrocytes cover the entire brain and spinal cord surface, exhibit an atypical morphology, and are evolutionarily conserved from zebrafish, rodents, and non-human primates to humans. Identification of this highly specialized astrocyte subtype will advance our understanding of CNS homeostasis and potentially be targeted for therapeutic intervention to combat peripheral inflammatory effects on the CNS.