Background and objectives: CSF biomarkers of Aβ42 and phosphorylated tau (p-tau181) are used clinically for the detection of Alzheimer disease (AD) pathology during life. CSF biomarker validation studies have largely used clinical diagnoses and/or amyloid PET imaging as the reference standard. The few existing CSF-to-autopsy studies have been restricted to late-stage AD. This CSF-to-autopsy study investigated associations between CSF biomarkers of AD and AD neuropathologic changes among brain donors who had normal cognition at the time of lumbar puncture (LP).
Methods: This was a retrospective study of brain donors from the National Alzheimer's Coordinating Center who had normal cognition at the time of LP and who had measurements of CSF Aβ42 and p-tau181 performed with Lumipulse assays. All brain donors were from Washington University Knight ADRC. Staging of AD neuropathologic change (ADNC) was made based on National Institute on Aging-Alzheimer's Association criteria. For this study, participants were divided into 2 categories: "AD-" (no AD/low ADNC) and "AD+" (intermediate/high ADNC). Accuracy of each biomarker for discriminating AD status was evaluated using area under the curve (AUC) statistics generated using predicted probabilities from binary logistic regressions that controlled for age, sex, APOE ε4, and interval between LP and death.
Results: The average age at LP was 79.3 years (SD = 5.6), and the average age at death was 87.1 years (SD = 6.5). Of the 49 brain donors, 24 (49%) were male and 47 (95.9%) were White. 20 (40.8%) had autopsy-confirmed AD. The average interval from LP until death was 7.76 years (SD = 4.31). CSF p-tau181/Aβ42 was the optimal predictor of AD, having excellent discrimination accuracy (AUC = 0.97, 95% CI 0.94-1.00, p = 0.003). CSF p-tau181 alone had the second-best discrimination accuracy (AUC = 0.92, 95% CI 0.84-1.00, p = 0.001), followed by CSF Aβ42 alone (AUC = 0.92, 95% CI 0.85-1.00, p = 0.007), while CSF t-tau had the numerically lowest discrimination accuracy (AUC = 0.87, 95% CI 0.76-0.97, p = 0.005). Effects remained after controlling for prevalent comorbid neuropathologies. CSF p-tau181/Aβ42 was strongly associated with CERAD ratings of neuritic amyloid plaque scores and Braak staging of NFTs.
Discussion: This study supports Lumipulse-measured CSF Aβ42 and p-tau181 and, particularly, the ratio of p-tau181 to Aβ42, for the early detection of AD pathophysiologic processes.
Classification of evidence: This study provides Class II evidence that Lumipulse measures of p-tau181/Aβ42 in the CSF accurately discriminated cognitively normal participants with and without Alzheimer disease neuropathologic change.
Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of several malignancies, with improved survival. These monoclonal antibodies target immune checkpoints, including cytotoxic T-lymphocyte-associated protein 4 (ipilimumab and tremelimumab), programmed death 1 (nivolumab, pembrolizumab, cemiplimab, and dostarlimab), programmed death ligand 1 (atezolizumab, avelumab, and durvalumab), and lymphocyte activation gene 3 (relatlimab), and effectively augment the immune response against tumor cells. Releasing the brakes on the immune system has consequences, however, in the form of immune-related adverse events (irAEs), which may affect any organ. Neurologic irAEs represent 1%-3% of all irAEs, with immune-mediated myopathy (ICI myopathy) being the most common manifestation. Recent large patient series and systematic reviews have established the key features and highlighted new insights into ICI myopathy. ICI myopathy is characterized by an acute or subacute onset of oculobulbar and/or proximal limb weakness, with or without associated respiratory insufficiency and myocarditis. Creatine kinase elevation is common. Oculobulbar presentations with or without respiratory failure may be misattributed to neuromuscular junction disorders, particularly because acetylcholine receptor antibodies are present in up to 40% of patients; however, an electrodiagnostic evidence of a defect of neuromuscular transmission is often absent even in patients with severe weakness, highlighting that the myopathic process is the driving force behind these presentations. Muscle histopathology commonly demonstrates a unique signature of multifocal clusters of necrotic and regenerating fibers, differentiating ICI myopathy from other autoimmune myopathies. Transcriptomic analysis has uncovered distinct subgroups within ICI myopathy, revealing varying degrees of type 1 and type 2 interferon pathway activation alongside notable upregulation of the interleukin (IL)-6 pathway in affected muscle tissue. This discovery presents a promising avenue for intervention through the use of therapies that suppress the interferon pathway and target IL-6 or its receptor. Despite clinical improvements with immunomodulatory therapy, with corticosteroids the mainstay of treatment, mortality remains high, particularly in those with associated myocarditis or respiratory failure requiring intubation, where mortality occurs in up to 50%. ICI withdrawal can lead to cancer progression and death, highlighting a need for improved approaches to ICI rechallenge, performed in limited patients with variable success to date.
Background and objectives: In patients with cerebral small vessel disease (SVD), impaired cerebrovascular reactivity (CVR) is related to worse concurrent SVD burden, but less is known about cerebrovascular reactivity and long-term SVD lesion progression and clinical outcomes. We investigated associations between cerebrovascular reactivity and 1-year progression of SVD features and clinical outcomes.
Methods: Between 2018 and 2021, we recruited patients from the Edinburgh/Lothian stroke services presenting with minor ischemic stroke and SVD features as part of the Mild Stroke Study 3, a prospective observational cohort study (ISRCTN 12113543). We acquired 3T brain MRI at baseline and 1 year. At baseline, we measured cerebrovascular reactivity to 6% inhaled CO2 in subcortical gray matter, normal-appearing white matter, and white matter hyperintensities (WMH). At baseline and 1 year, we quantified SVD MRI features, incident infarcts, assessed stroke severity (NIH Stroke Scale), recurrent stroke, functional outcome (modified Rankin Scale), and cognition (Montreal Cognitive Assessment). We performed linear and logistic regressions adjusted for age, sex, and vascular risk factors, reporting the regression coefficients and odds ratios with 95% CIs.
Results: We recruited 208 patients of whom 163 (mean age and SD: 65.8 ± 11.2 years, 32% female) had adequate baseline CVR and completed the follow-up structural MRI. The median increase in WMH volume was 0.32 mL with (Q1, Q3) = (-0.48, 1.78) mL; 29% had a recurrent stroke or incident infarct on MRI. At 1 year, patients with lower baseline cerebrovascular reactivity in normal-appearing tissues had increased WMH (regression coefficient: B = -1.14 [-2.13, -0.14] log10 (%ICV) per %/mm Hg) and perivascular space volumes (B = -1.90 [-3.21, -0.60] log10 (%ROIV) per %/mm Hg), with a similar trend in WMH. CVR was not associated with clinical outcomes at 1 year.
Discussion: Lower baseline cerebrovascular reactivity predicted an increase in WMH and perivascular space volumes after 1 year. CVR should be considered in SVD future research and intervention studies.
Background and objectives: Lance-Adams syndrome (LAS), or chronic posthypoxic myoclonus, is a long-term disabling neurologic disorder occurring in survivors of anoxia. The cortical or subcortical origin of this myoclonus is unclear. We aimed to identify the neuroanatomical origin of myoclonus in LAS.
Methods: We conducted a cross-sectional study and investigated patients diagnosed with LAS from the Department of Neurology of Pitié-Salpêtrière Hospital, using multimodal neurologic explorations: EEG with quantitative analyses, polygraphic EMG recording of myoclonus, coupled EEG-EMG analyses with jerk-locked back averaging, and 18fluorodeoxyglucose PET/CT imaging.
Results: All 18 patients had action multifocal or generalized myoclonus. Eleven patients also presented seizures, mainly generalized tonic-clonic seizures. For 8 patients, myoclonus decreased after seizures for a variable duration, from 1 day to 2 weeks. Epileptiform discharges were identified over the central median region (n = 14), with a maximal amplitude on the Cz (65 ± 20 µV, n = 12) and Fz (107 µV, n = 1) electrodes, and a significantly increased frequency during non-rapid eye movement sleep stages 1 (12 ± 8.5 events/minute, p = 0.004, n = 9) and 2 (11 ± 8.8 events/minute, p = 0.016, n = 7) compared with wake (5.5 ± 5.4 events/minute). The duration of the cortical and muscular events was significantly and positively correlated (ρ = 0.58, p < 0.001, n = 9). Action myoclonic jerks with a duration of <50 ms were confirmed in all patients, with a fast-descending corticospinal way organization with a mean biceps brachii-first interossei dorsalis delay of 9.8 ± 1 ms (n = 8). A central cortical transient preceding the muscular jerks was identified (n = 14), with a mean latency of -31.9 ± 2.9 ms for the tibialis anterior muscle (n = 7). A regional metabolism decrease was observed in the precentral cortex, supplementary motor area, paracentral lobule (n = 6), and postcentral cortex and precuneus (n = 5). This metabolism decrease was bilateral in the precentral cortex for 83% of the patients and in the postcentral cortex for 100%. Hypometabolism in the precentral, supplementary motor, and postcentral areas was confirmed with a voxelwise analysis (p < 10-3, n = 6).
Discussion: Our findings, based on a large cohort of patients with LAS, strongly suggest a cortical myoclonus, originating within the motor cortex and related to epileptiform mechanisms.
Two protocadherins, Dachsous and Fat, regulate organ growth in Drosophila via the Hippo pathway. Dachsous and Fat bind heterotypically to regulate the abundance and subcellular localization of a "core complex" consisting of Dachs, Dlish, and Approximated. This complex localizes to the junctional cortex where it represses Warts. Dachsous is believed to promote growth by recruiting and stabilizing this complex, while Fat represses growth by promoting its degradation. Here, we examine the functional relationships between the intracellular domains of Dachsous and Fat and the core complex. While Dachsous promotes the accumulation of core complex proteins in puncta, it is not required for their assembly. Indeed, the core complex accumulates maximally in the absence of both Dachsous and Fat. Furthermore, Dachsous represses growth in the absence of Fat by removing the core complex from the junctional cortex. Fat similarly recruits core complex components but promotes their degradation. Our findings reveal that Dachsous and Fat coordinately constrain tissue growth by repressing the core complex.
Efficient import of nuclear-encoded proteins into mitochondria is crucial for proper mitochondrial function. The conserved translation factor eIF5A binds ribosomes, alleviating stalling at polyproline-encoding sequences. eIF5A impacts mitochondrial function across species, though the precise molecular mechanism is unclear. We found that eIF5A depletion in yeast reduces the translation and levels of the TCA cycle and oxidative phosphorylation proteins. Loss of eIF5A causes mitoprotein precursors to accumulate in the cytosol and triggers a mitochondrial import stress response. We identify an essential polyproline protein as a direct target of eIF5A: the mitochondrial inner membrane protein and translocase component Tim50. Thus, eIF5A controls mitochondrial protein import by alleviating ribosome stalling along Tim50 mRNA at the mitochondrial surface. Removal of polyprolines from Tim50 partially rescues the mitochondrial import stress response and translation of oxidative phosphorylation genes. Overall, our findings elucidate how eIF5A impacts the mitochondrial function by promoting efficient translation and reducing ribosome stalling of co-translationally imported proteins, thereby positively impacting the mitochondrial import process.
Successful axonal regeneration following injury requires the effective allocation of energy. How axons withstand the initial disruption in mitochondrial energy production caused by the injury and subsequently initiate regrowth is poorly understood. Transcriptomic data showed increased expression of glycolytic genes after optic nerve crush in retinal ganglion cells with the co-deletion of Pten and Socs3. Using retinal cultures in a multicompartment microfluidic device, we observed increased regrowth and enhanced mitochondrial trafficking in the axons of Pten and Socs3 co-deleted neurons. While wild-type axons relied on mitochondrial metabolism, after injury, in the absence of Pten and Socs3, energy production was supported by local glycolysis. Specific inhibition of lactate production hindered injury survival and the initiation of regrowth while slowing down glycolysis upstream impaired regrowth initiation, axonal elongation, and energy production. Together, these observations reveal that glycolytic ATP, combined with sustained mitochondrial transport, is essential for injury-induced axonal regrowth, providing new insights into the metabolic underpinnings of axonal regeneration.
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