Faculty Bibliography

OBJECTIVE:Prolonged post-stroke cardiac rhythm monitoring (PCM) reveals a substantial proportion of ischemic stroke (IS) patients with atrial fibrillation (AF) not detected by conventional rhythm monitoring strategies. We aim to evaluate the association between PCM and the institution of stroke preventive strategies and stroke recurrence. METHODS:We searched MEDLINE and SCOPUS databases to identify studies reporting stroke recurrence rates in patients with history of recent IS or transient ischemic attack (TIA) receiving PCM compared with patients receiving conventional cardiac rhythm monitoring. Pairwise meta-analyses were performed under the random-effects model. To explore for differences between the monitoring strategies we combined direct and indirect evidence for any given pair of monitoring devices assessed within a randomized controlled trial (RCT). RESULTS:We included 8 studies (5 RCTs, 3 observational; 2994 patients). Patients receiving PCM after their index event had a higher rate of AF detection and anticoagulant initiation in both RCTs (RR=3.91, 95%CI:2.54-6.03 & RR=2.16, 95%CI:1.66-2.80) and observational studies (RR=2.06, 95%CI:1.57-2.70 & RR=2.01; 95%CI:1.43-2.83), respectively. PCM was associated with a lower risk of recurrent stroke during follow-up in observational studies (RR=0.29; 95%CI:0.15-0.59), but not in RCTs (RR=0.72, 95%CI:0.49-1.07). In the indirect analyses of RCTs the likelihood of AF detection and anticoagulation initiation was higher for implantable loop recorders compared with both Holter monitors and external loop recorders. CONCLUSIONS:PCM after an IS or TIA can lead to higher rates of AF detection and anticoagulant initiation. Currently, there is no solid RCT evidence supporting that PCM may be associated with lower stroke recurrence risk.

BACKGROUND:Preclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by small (<1 °C) decreases in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults. METHODS:Tb was continuously measured with ingestible telemetry sensors for 48-h. This period also included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later. RESULTS:Lower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF Ptau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05). CONCLUSIONS:These results, the first available for human, suggest that lower Tb in older adults may be associated with increased soluble and aggregated tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation. CLINICAL TRIAL NUMBER/BACKGROUND:NCT03053908.

BACKGROUND:Delayed-onset of headache seems a specific feature of cerebrovascular events after COVID-19 vaccines. METHODS:All consecutive events reported to the United States Vaccine Adverse Reporting System following COVID-19 vaccines (1 January to 24 June 2021), were assessed. The timing of headache onset post-vaccination in subjects with and without concomitant cerebrovascular events, including cerebral venous thrombosis, ischemic stroke, and intracranial haemorrhage was analysed. The diagnostic accuracy in predicting concurrent cerebrovascular events of the guideline- proposed threshold of three-days from vaccination to headache onset was evaluated. RESULTS:There were 314,610 events following 306,907,697 COVID-19 vaccine doses, including 41,700 headaches, and 178/41,700 (0.4%) cerebrovascular events. The median time between the vaccination and the headache onset was shorter in isolated headache (1 day vs. 4 (in cerebral venous thrombosis), 3 (in ischemic stroke), or 10 (in intracranial hemorrhage) days, all P < 0.001). Delayed onset of headache had an area under the curve of 0.83 (95% CI: 0.75-0.97) for cerebral venous thrombosis, 0.70 (95% CI: 0.63-76) for ischemic stroke and 0.76 (95% CI: 0.67-84) for intracranial hemorrhage, and >99% negative predictive value. CONCLUSION/CONCLUSIONS:Headache following COVID-19 vaccination occurs within 1 day and is rarely associated with cerebrovascular events. Delayed onset of headache 3 days post-vaccination was an accurate diagnostic biomarker for the occurrence of a concomitant cerebrovascular events.

There is an unmet need to develop practical methods for differentiating multiple sclerosis (MS) from other neuroinflammatory disorders using standard brain MRI. To develop a practical approach for differentiating MS from neuromyelitis optica spectrum disorder (NMOSD) and MOG antibody-associated disorder (MOGAD) with brain MRI, we first identified lesion locations in the brain that are suggestive of MS-associated demyelination ("MS Lesion Checklist") and compared frequencies of brain lesions in the "MS Lesion Checklist" locations in a development sample of patients (n = 82) with clinically definite MS, NMOSD, and MOGAD. Patients with MS were more likely than patients with non-MS to have lesions in 3 locations only: anterior temporal horn (p < 0.0001), periventricular ("Dawson's finger") (p < 0.0001), and cerebellar hemisphere (p = 0.02). These three lesion locations were used as predictor variables in a multivariable regression model for discriminating MS from non-MS. The model had area under the curve (AUC) of 0.853 (95% confidence interval: 0.76-0.945), sensitivity of 87.1%, and specificity of 72.5%. We then used an independent validation sample with equal representation of MS and NMOSD/MOGAD cases (n = 97) to validate our prediction model. In the validation sample, the model was 76.3% accurate in discriminating MS from non-MS. Our simple method for predicting MS versus NMOSD/MOGAD only requires a neuroradiologist or clinician to ascertain the presence of lesions in three locations on conventional MRI sequences. It can therefore be readily applied in the real-world setting for training and clinical practice.

Background Vascular function is compromised in Alzheimer disease (AD) years before amyloid and tau pathology are detected and a substantial body of work shows abnormal platelet activation states in patients with AD. The aim of our study was to investigate whether platelet function in middle age is independently associated with future risk of AD. Methods and Results We examined associations of baseline platelet function with incident dementia risk in the community-based FHS (Framingham Heart Study) longitudinal cohorts. The association between platelet function and risk of dementia was evaluated using the cumulative incidence function and inverse probability weighted Cox proportional cause-specific hazards regression models, with adjustment for demographic and clinical covariates. Platelet aggregation response was measured by light transmission aggregometry. The final study sample included 1847 FHS participants (average age, 53.0 years; 57.5% women). During follow-up (median, 20.5 years), we observed 154 cases of incident dementia, of which 121 were AD cases. Results from weighted models indicated that platelet aggregation response to adenosine diphosphate 1.0 µmol/L was independently and positively associated with dementia risk, and it was preceded in importance only by age and hypertension. Sensitivity analyses showed associations with the same directionality for participants defined as adenosine diphosphate hyper-responders, as well as the platelet response to 0.1 µmol/L epinephrine. Conclusions Our study shows individuals free of antiplatelet therapy with a higher platelet response are at higher risk of dementia in late life during a 20-year follow-up, reinforcing the role of platelet function in AD risk. This suggests that platelet phenotypes may be associated with the rate of dementia and potentially have prognostic value.

Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (AB) for growth and survival in the brain parenchyma. Melanoma-secreted AB activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of AB decreases brain metastatic burden.

Background/Significance: Catatonia is common in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (Espinola-Nadurille, 2019). The glutamate NMDAR antagonists amantadine and memantine are effective in catatonia (Beach, 2017), but data on their use in anti-NMDAR encephalitis is limited. We describe three patients with catatonia due to anti-NMDAR encephalitis treated with NMDAR antagonists and propose a possible mechanism underlying differential outcomes. Case 1: A 20-year-old woman presented with catatonic symptoms after successful treatment of anti-NMDAR encephalitis with immunotherapy and salpingo-oopherectomy for ovarian teratoma. Initial Bush-Francis Catatonia Rating Scale (BFCRS) score was 22. Lorazepam 2.5 mg three times daily was partially effective, but increased doses caused sedation. Memantine was titrated to 10 mg twice daily with complete resolution of catatonia over two weeks. Case 2: A 26-year-old woman presented with catatonic with BFCRS score of 25, after successful immunotherapy for anti-NMDAR encephalitis. Lorazepam 2 mg four times daily was partially effective, but further increase caused respiratory depression. Memantine 10 mg daily resulted in further improvement. Lorazepam titration to 4 mg four times daily was then possible, with complete resolution of catatonia over two weeks. Case 3: A 31-year-old woman with anti-NMDAR encephalitis presented with catatonic symptoms with BFCRS score of 22, after a hospital course significant for limited response to immunotherapy with persistently elevated serum anti-NMDAR antibody titers. Lorazepam 2 mg three times daily was partially effective, but further increase caused sedation. Both amantadine 100 mg twice daily and memantine 10 mg were trialed but were discontinued due to agitation. Mutism and negativism persisted, with a discharge BFCRS score of 12.
Discussion(s): Memantine was effective for catatonia and well tolerated in two patients with successfully treated anti-NMDAR encephalitis, but both amantadine and memantine caused agitation in a third patient with active disease. NMDARs are reversibly internalized in the presence of anti-NMDAR antibodies, leading to a compensatory increase in downstream glutamatergic tone. We hypothesize that NMDAR reemergence after successful treatment, in the context of excess extracellular glutamate, creates a state of excitotoxicity contributing to catatonic signs for which NMDAR blockade can be effective. In the third case, where NMDARs presumably remained internalized in the presence of persistent anti-NMDAR antibodies and a state of NMDAR hypofunction persisted, further NMDAR blockade caused clinical worsening. Conclusion/Implications: NMDAR antagonists can be safe and effective in patients with residual catatonia following successful treatment of anti-NMDAR encephalitis but may be less useful during active disease. More work is needed to clarify best practices for patients with catatonia due to anti-NMDAR encephalitis. References: 1. Espinola-Nadurille M, Flores-Rivera J, Rivas-Alonso V, et al. Catatonia in patients with anti-NMDA receptor encephalitis. Psychiatry Clin Neurosci. 2019;73(9):574-580. 2. Beach SR, Gomez-Bernal F, Huffman JC, Fricchione GL. Alternative treatment strategies for catatonia: A systematic review. Gen Hosp Psychiatry. 2017;48(June):1-19.
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PURPOSE/OBJECTIVE:A device that provides continuous, long-term, accurate seizure detection information to providers and patients could fundamentally alter epilepsy care. Subgaleal (SG) EEG is a promising modality that offers a minimally invasive, safe, and accurate means of long-term seizure monitoring. METHODS:Subgaleal EEG electrodes were placed, at or near the cranial vertex, simultaneously with intracranial EEG electrodes in 21 epilepsy patients undergoing intracranial EEG studies for up to 13 days. A total of 219, 10-minute single-channel SGEEG samples, including 138 interictal awake or sleep segments and 81 seizures (36 temporal lobe, 32 extra-temporal, and 13 simultaneous temporal/extra-emporal onsets) were reviewed by 3 expert readers blinded to the intracranial EEG results, then analyzed for accuracy and interrater reliability. RESULTS:Using a single-channel of SGEEG, reviewers accurately identified 98% of temporal and extratemporal onset, intracranial, EEG-verified seizures with a sensitivity of 98% and specificity of 99%. All focal to bilateral tonic--clonic seizures were correctly identified. CONCLUSIONS:Single-channel SGEEG, placed at or near the vertex, reliably identifies focal and secondarily generalized seizures. These findings demonstrate that the SG space at the cranial vertex may be an appropriate site for long-term ambulatory seizure monitoring.

BACKGROUND:Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is characterized by progressive memory loss and cognitive impairment. Our understanding of AD pathogenesis is limited and no effective disease-modifying treatment is available. Mitochondria are cytoplasmic organelles critical to the homeostatic regulation of glucose and energy in the cell. METHODS:Mitochondrial abnormalities are found early in the course of AD and dysfunctional mitochondria are involved in AD progression. The resulting respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species are highly damaging to neurons. Restoration of mitochondrial function may provide a novel therapeutic strategy for AD. RESULTS:This review discusses the specifics of mitochondrial fragmentation, imbalances in fission and fusion, and DNA damage seen in AD and the contribution of compromised mitochondrial activity to AD etiopathogenesis. It explores how an understanding of the processes underlying mitochondrial failure may lead to urgently needed treatment innovations. It considers individual mitochondrial proteins that have emerged as promising drug targets and evaluates neuroprotective agents that could improve the functional state of mitochondria in the setting of AD. CONCLUSIONS:There is great promise in exploring original approaches to preserving mitochondrial viability as a means to achieve breakthroughs in treating AD.