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Abstract Background The objective of this study was to determine the predictive value of amyloid‐PET versus plasma %p‐tau217 (defined as the ratio of phosphorylated to non‐phosphorylated Tau217 × 100), Aβ42/40, and the amyloid probability score (APS2; which combines of Aβ42/40 and %p‐tau217) in tau‐PET transitions (T‐ to T+). Method Participants included were from the Mayo Clinic Study of Aging (MCSA) and had plasma markers measured by mass spectrometry (IP‐MS; C2N), had an amyloid‐PET scan, and had a tau‐PET negative scan (SUVR<1.29, temporal meta‐ROI) at the baseline, along with one or more follow‐up tau‐PET scans. Cox proportional hazard models were used to evaluate the relationship between C2N plasma %P‐Tau217 and APS2 and incident tau‐PET positivity (SUVR>=1.29) adjusting for age, sex, and APOE ε4. An analysis was also performed using amyloid‐PET centiloid as the predictor. Both the plasma markers and amyloid‐PET centiloid were scaled so that a one‐unit change corresponds to the respective interquartile range (IQR) for comparability of hazard ratios (HR). The analyses were repeated in the BioFINDER‐2 cohort for validation. Result 255 MCSA participants (122 female [47.8%] were included with a median age of 71.9 (IQR: 65.8, 78.8) years old, of which 37 progressed to tau‐PET positivity. At baseline, 238 (93.7%) were cognitively unimpaired. Higher baseline %p‐tau217 (HR: 1.52 [95% CI: 1.28, 1.8]), amyloid‐PET centiloid (HR: 1.47 [95% CI: 1.20, 1.79]), and APS2 (HR: 1.62 [95% CI: 1.22, 2.16]) were associated with an increased risk of progressing to tau‐PET positive (Figure 1). Aβ42/40 (HR: 1.06 [95% 0.604–1.867] was not associated with incident tau positivity Among 605 participants who were tau negative at index date in BioFINDER‐2 (316 (52.2%) cognitively unimpaired), with a median age of 70.2 (IQR: 60.5‐76.4), 33 progressed to tau positivity with higher %p‐tau217 (HR: 1.8 [95% CI: 1.5, 2.17]), amyloid‐PET centiloid (HR: 2.3 [95% CI: 1.77, 2.97]), and lower Aβ 42/40 (HR: 0.42 [95% CI: 0.21, 0.85]) at index date all associated with an increased risk of progressing to tau‐PET positive. Conclusion In two independent cohorts , %p‐tau217 provides predictive information about those who will convert from tau negative to tau positive on PET scan with the associations being similar to amyloid‐PET.

Abstract Background Although Alzheimer's disease (AD) is classically defined by the accumulation of tau neurofibrillary tangles and Aβ plaques, a large proportion of cases are also positive for inclusions containing TAR DNA binding protein of 43 kDa (TDP‐43) – and evidence shows that these cases generally have a more aggressive disease course marked by worse memory and increased hippocampal atrophy. As we advance towards precision medicine in AD, it is imperative that we understand the contribution of TDP‐43 proteinopathy to pathogenesis and develop tools to track this pathology in living patients. Methods In affected neurons, TDP‐43 nuclear clearance triggers mRNA misprocessing events including cryptic exon inclusion and alternative polyadenylation. We aim to exploit these events to develop sensitive biomarkers that can serve as proxy measures for TDP‐43 dysfunction. As we identify misprocessed TDP‐43 targets that accumulate in affected brain regions in AD, we also explore the impact of these aberrant transcripts on molecular processes and pathways in the brain to gain insight into disease pathomechanisms. Results We have developed tools to measure a promising biomarker of TDP‐43 dysfunction, a cryptic form of the protein HDGFL2, and verified that it can be detected in post‐mortem AD patient tissue specifically in brain regions marked by mixed pathology. We have also uncovered a connection between TDP‐43 dysfunction and compromised endolysosomal activity. In fact, we find that artificially severing the endolysosomal pathway via expression of a constitutively active Rab5 can induce TDP‐43 pathology and neurodegeneration in vivo in mice, and we are using this tool to map the consequences of endolysosomal dysfunction in the brain and its potential connection to mixed pathology formation in AD. Conclusions TDP‐43 co‐pathology has a profound effect on AD pathogenesis that may be intrinsically linked to a disruption of the endolysosomal pathway in neurons. Exploring the consequences of TDP‐43 dysfunction in the brain can open new avenues for AD biomarker and therapeutic development.

Abstract Background Standardizing tau pathology quantification in vivo is challenged by inherent characteristics of tau‐PET tracers. The HEAD study aims to generate a leading, longitudinal head‐to‐head dataset of MK‐6240, Flortaucipir, RO948, and PI‐2620 tau‐PET to harmonize tracers' outcomes and develop tools to generalize findings across studies and trials. Here, we provide an update on the progression of the HEAD study. Method HEAD is a multicentric study comprising nine performance sites. Recruitment aimed for 620 individuals between 18‐28 or 50‐90 years, classified as Young/CU/MCI/Dementia. The HEAD protocol involves clinical assessment utilizing the NACC Uniform Data Set, blood collection for banking of plasma/serum/buffy coat/whole blood, and MRI acquisition based on ADNI4. All participants undergo amyloid‐PET with either PiB/NAV4694/Florbetaben/Flutemetamol. All undergo head‐to‐head tau‐PET with at least two tracers, including MK‐6240 (90‐110), Flortaucipir (80‐100), PI‐2620 (45‐75), and RO948 (70‐90). PET data is reconstructed and processed uniformly similarly to ADNI4. The Laboratory of Neuroimaging (LONI) provides centralized databasing, and the National Centralized Repository for ADRD (NCRAD) provides the blood biorepository for all samples. All study procedures are repeated at 18 months. Result Over 26 months, N = 679 participants were enrolled into HEAD, exceeding our proposed enrollment by 9.5%. Mean age of older adults is 72.1 years, female distribution is 54%, and 24% of individuals are from underrepresented groups (race/ethnicity/rurality). Progression in data collection has led to N = 551 (81%) of enrolled participants having a completed initial timepoint, and 1,489 total acquired head‐to‐head tau‐PET scans (mean acquisition window=34.9 days). Clinical characteristics including group distribution, APOEε4 carriership, plasma biomarker distribution (Aβ42/40 ratio/NfL/GFAP/PTau217), consensus visual rating of amyloid‐PET, and Braak stage classification are summarized in Figure 1. Two representative cases (CU/AD) of head‐to‐head tau‐PET with four tau tracers are shown in Figure 2. Longitudinal data collection has been initiated in N = 95 participants. Figure 3. demonstrates two cases (CU/MCI) of 18‐month longitudinal head‐to‐head tau‐PET with MK‐6240 and Flortaucipir. Conclusion The HEAD study cohort represents a continued effort in the optimization of AD imaging biomarkers. Cross‐sectional and longitudinal data collection in HEAD are ongoing, in addition to comprehensive plasma biomarker measurements. Generation of findings from HEAD cohort data will provide novel and crucial guidance on the use of tau‐PET tracers.

Objective: To compare the prevalence and patterns of transverse sinus stenosis (TSS) in patients with lateral skull base spontaneous cerebrospinal fluid (sCSF) leaks and idiopathic intracranial hypertension (IIH), to clarify its role in leak pathogenesis and implications for venous-directed therapies. Study design: Retrospective case-control study. Setting: Single tertiary care institution. Patients: Adults with lateral skull base sCSF leaks confirmed by clinical, laboratory, or surgical findings, and adults with IIH without cranial CSF leaks meeting Modified Dandy criteria. Intervention: Independent magnetic resonance venography evaluation by 2 fellowship-trained neuroradiologists. Main outcome measures: Presence, laterality, and severity of TSS. Results: Eighteen patients with sCSF leaks and 78 patients with IIH were included. The rate of individual TSS, including both unilateral and bilateral cases, was higher in the IIH cohort than in the sCSF leak cohort (bilateral TSS: n=66, 84.6% vs. n=6, 33.3%; P <0.001). Severe bilateral TSS was observed more in the IIH cohort (n=40, 51.3%) compared with the sCSF leak cohort (n=1, 5.6%; P <0.001). Conclusions: Though patients with lateral skull base sCSF leaks have TSS, the significantly lower rate compared with patients with IIH suggests that TSS may play a lesser role in the pathogenesis of lateral skull base defects. These findings indicate that the role of transverse sinus stenting in lateral skull base sCSF leaks remains uncertain and highlight the need to further investigate local remodeling processes when considering the role of venous sinus stenting in this population.

Background and importance Renal colic pain is typically managed using intravenous opioids, but the intranasal route has emerged as a less invasive and time-efficient alternative. Intranasal ketamine has shown promise as a safe and effective analgesic for acute pain in emergency settings. Objective To compare the efficacy and safety of intranasal ketamine versus intravenous opioids for renal colic pain management in the emergency department. Design, settings, and participants PubMed, Embase, and Cochrane were systematically searched for randomized controlled trials (RCTs) comparing intranasal ketamine to intravenous morphine or intravenous fentanyl in patients with renal colic. Intervention or exposure Intranasal ketamine as the primary intervention; comparators were intravenous morphine or fentanyl. Outcomes, measure, and analysis The primary outcome was pain intensity at various time points, measured using the Visual Analog Scale (VAS) and Numerical Rating Scale (NRS). Secondary outcomes: need for rescue analgesia, incidence of adverse events, nausea, and dizziness. Data were pooled using random-effects models to calculate mean differences for continuous outcomes and risk ratios for binary outcomes, with 95% confidence intervals (CIs). All statistical analyses were performed using R Software, version 4.2.3. Main results We included four RCTs, involving 454 patients, of whom 230 (50.6%) received intranasal ketamine. There were no significant differences between groups in pain scores at 5 min (mean difference: −0.41 VAS/NRS, 95% CI: −1.88 to 1.07, P = 0.59), 15 min (mean difference: −0.20 VAS/NRS, 95% CI: −0.86 to 0.46, P = 0.56), and 30 min (mean difference: 0.53 VAS/NRS, 95% CI: −0.08 to 1.13, P = 0.09). No significant differences were found between groups in the need for rescue analgesia or in the incidence of adverse events, nausea, or dizziness. Conclusion Intranasal ketamine demonstrated analgesic efficacy comparable to intravenous opioids at 5, 15, and 30 min, with no increase in adverse events or rescue analgesia requirements.

Abstract Immune checkpoint inhibitors (ICI) have transformed cancer therapy but can induce a spectrum of endocrine complications. Acquired generalized lipodystrophy (AGL) is a rare adverse effect, leading to severe metabolic derangements including insulin-resistant diabetes, dyslipidemia, and hepatic steatosis. Marked hypoleptinemia is noted in these patients, and leptin-replacement therapy is known to be beneficial in patients with other forms of AGL. Though rare, T-cell lymphoma has been reported in patients with AGL on leptin therapy, and there has been much debate on the association between hyperleptinemia and cancer. The safety and efficacy of leptin therapy in patients with ICI-induced AGL and cancer are therefore not clear. We report a 66-year-old woman with metastatic lung adenocarcinoma who developed multiple endocrine disorders including AGL with metabolic abnormalities following pembrolizumab therapy. Initiation of daily metreleptin led to marked improvement in dyslipidemia, glycemic control, and hepatic steatosis, with no evidence of cancer recurrence after 2 years of leptin-replacement therapy. While further studies are warranted to establish the long-term efficacy and safety of leptin in ICI-induced AGL patients with a history of malignancy, this case report provides useful information for the management of these rare, challenging patients.

Miller et al. maintain that thalamic SEEG can now be considered a cornerstone of standard clinical practice in individualized epilepsy care, helping to define seizure onset and spread, assess therapeutic stimulation, map connectivity, and identify target-specific biomarkers for responsive neurostimulation.