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Introduction Up to 18% of spontaneous intracerebral hemorrhages are cryptogenic despite a thorough workup, usually noted in a lobar location. Although undetected on DSA, a significant proportion of these represent ruptured micro‐AVM/AVF or cavernous malformations that ultimately are amenable to surgical resection if detected on biopsy. However, occult cerebral amyloid angiopathy can also present similarly, and their management is markedly different. Methods We present a case of recurrent bilateral medial frontal hemorrhage in a patient without known cerebrovascular disease that evaded diagnosis despite hematologic evaluation, MRI, CTA, two DSAs, three clot evacuations with pathology, and brain biopsy. Results The patient is a 60‐year‐old previously healthy woman who presented with sudden onset right hemiparesis and speech arrest. CT revealed a left parasagittal hemorrhage. She was brought to the OR for clot evacuation. Pathology from the clot revealed blood vessels of multiple sizes consistent with meningeal vessels or underlying AVM/AVF. A 6‐vessel cerebral angiogram as unremarkable. The patient’s inpatient course was complicated by new onset Afib with RVR and asymptomatic DVT with PE, however no etiology of coagulopathy was detected. MRI brain showed no evidence of cerebral microbleed or other underlying pathology, noting only DWI + FLAIR hyperintensity in the left ACA territory. The patient was diagnosed with ACA territory stroke complicated by PH2‐type hemorrhagic conversion. She was initially placed on IV Heparin, before transition to apixaban uneventfully. She continued to recover in the hospital and was eventually discharged to rehab. She re‐presented 1 month later with worsening behavioral arrest and right hemiparesis. CT head revealed recurrence of left parasagittal ICH. She underwent clot evacuation in the OR again and repeat pathology was unrevealing. A repeat MRI showed only the evident bleed and a subtle hyperintensity in the right occipital cortex suspicious for an interval subacute occipital lobe stroke with laminar necrosis, ostensibly from Afib. She improved clinically and was discharged to rehab with a diagnosis of recurrent hemorrhage attributed to anticoagulant use and recent stroke. She was discharged this time on no anticoagulant or antiplatelets. She re‐presented 1 month later with sudden onset speech arrest, but now with left hemiparesis. CT revealed a right parasagittal hemorrhage. She was brought to the OR for emergent clot evacuation and parenchymal biopsy – which was initially normal. A repeat 6‐vessel DSA was again unremarkable as was repeat brain MRI. The patient’s parenchymal biopsy was sent for specific congo‐red and immunohistochemistry for beta‐amyloid. IHC revealed beta‐amyloid plaques in the parenchyma and vessel walls, confirming a diagnosis of CAA. Conclusion Apparently cryptogenic lobar hemorrhage may be caused by both occult micro‐AVM/fistula and CAA. As in this case, when a patient experiences recurrent DSA negative lobar hemorrhages, biopsy should be pursued. This case was particularly challenging given the anatomical plausibility of parasagittal AVM/fistula given its midline location and venous drainage, considering the patient’s evident predisposition to systemic venous thrombosis hemorrhagic venous infarction mimicking lobar ICH is also possible. We present this case to raise awareness of the potential need for early biopsy, especially in patients who may also require anticoagulation or antiplatelet medications.

Abstract Nicotinic acetylcholine receptors (nAChRs) are broadly expressed in the central and peripheral nervous systems, playing essential roles in cholinergic neurotransmission. The lynx family proteins, a subset of the Ly6/uPAR superfamily expressed in multiple brain regions, have been shown to bind to nAChRs and modulate their function via allosteric regulation. The binding interactions between lynx and nAChRs, however, have not been systematically quantified and compared. In this work, we characterized the interactions between lynx1 or lynx2 and α3β4‐ or α7‐nAChRs using single‐molecule atomic force microscopy (AFM). The AFM technique allows the quantification of the off‐rate of lynx‐nAChR binding and of the energetic barrier width between the bound state and transition state, providing a biophysical means to compare the selectivity of lynx proteins for nAChR subtypes. Results indicate that lynx1 has a marginal preference for α7‐ over α3β4‐nAChRs. Strikingly, lynx2 exhibits a two order of magnitude stronger affinity for α3β4‐ compared to α7‐nAChRs. Together, the AFM assay serves as a valuable tool for the biophysical characterization of lynx‐nAChR binding affinities. Revealing the differential affinities of lynx proteins for nAChR subtypes will help elucidate how lynx regulates nAChR‐dependent functions in the brain, including nicotine addiction and other critical pathways.