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BACKGROUND: Suprasellar masses commonly include craniopharyngiomas and pituitary adenomas. Suprasellar glioblastoma is exceedingly rare with only a few prior case reports in the literature. Suprasellar glioblastoma can mimic craniopharyngioma or other more common suprasellar etiologies preoperatively. OBSERVATIONS: A 65-year-old male with no significant history presented to the emergency department with a subacute decline in mental status. Work-up revealed a large suprasellar mass with extension to the right inferior medial frontal lobe and right lateral ventricle, associated with significant vasogenic edema. The patient underwent an interhemispheric transcallosal approach subtotal resection of the interventricular portion of the mass. Pathological analysis revealed glioblastoma, MGMT partially methylated, with a BRAF V600E mutation. LESSONS: Malignant glioblastomas can mimic benign suprasellar masses and should remain on the differential for a diverse set of brain masses with a broad range of radiological and clinical features. For complex cases accessible from the ventricle where the pituitary complex cannot be confidently preserved via a transsphenoidal approach, an interhemispheric approach is also a practical initial surgical option. In addition to providing diagnostic value, molecular profiling may also reveal therapeutically significant gene alterations such as BRAF mutations.
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ABSTRACT: Suicide rapidly increased in the United States by 30% from 2000 to 2020, accounting for more than 800,000 deaths ( Neurosci Res Program Bull . 1972; 10: 384-8). Studies have shown that there are a multitude of underlying issues, including mental illness, that elevate an individual's risk of dying by suicide ( CDC WONDER: Underlying cause of death, 1999-2019 . Atlanta, GA: US Department of Health and Human Services, CDC; 2020). Presented here is a case of Bing Neel syndrome (BNS) found in a 69-year-old man who died by suicide by jumping off a 135' bridge. His medical history was significant for traumatic brain injury, Waldenstrom macroglobulinemia (WM), major depressive disorder, suicidal ideation, and anxiety. Bing Neel syndrome is a rare central nervous system complication of WM. His wife reported an abrupt mental deterioration starting 5 years before his death, characterized by paranoia, depression, and insomnia. He had been a high-functioning university professor. His decline culminated with the loss of independence in his activities of daily living. At autopsy, it was found that he experienced blunt force injuries related to the fall, causing his death. A neuropathologic examination revealed a brisk and fulminant clonal CD20 + /immunoglobulin M+ lymphocytic infiltrate, involving all sampled regions of his brain, consistent with WM. This workup was critical to obtaining an accurate pathologic diagnosis of BNS and understanding his full clinical status before death. Although BNS was not the proximate cause of death, this diagnosis aided the death investigation as a causal factor in his suicidality and was vital to providing his family closure.
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Trastorno Depresivo Mayor , Trastornos Psicóticos , Suicidio , Macroglobulinemia de Waldenström , Humanos , Masculino , Animales , Bovinos , Anciano , Ideación Suicida , Actividades Cotidianas , Macroglobulinemia de Waldenström/complicaciones , Macroglobulinemia de Waldenström/diagnóstico , Macroglobulinemia de Waldenström/patología , Trastornos Psicóticos/complicacionesRESUMEN
This study investigated the prevalence of embryonic and connective tissue elements in the filum terminale (FT) of patients with tethered cord syndrome (TCS), examining both typical and pathological histology. The FT specimens from 288 patients who underwent spinal cord detethering from 2013 to 2021 were analyzed. The histopathological examination involved routine hematoxylin and eosin staining and specific immunohistochemistry when needed. The patient details were extracted from electronic medical records. The study found that 97.6% of the FT specimens had peripheral nerves, and 70.8% had regular ependymal cell linings. Other findings included ependymal cysts and canals, ganglion cells, neuropil, and prominent vascular features. Notably, 41% showed fatty infiltration, and 7.6% had dystrophic calcification. Inflammatory infiltrates, an underreported finding, were observed in 3.8% of the specimens. The research highlights peripheral nerves and ganglion cells as natural components of the FT, with ependymal cell overgrowth and other tissues potentially linked to TCS. Enlarged vessels may suggest venous congestion due to altered FT mechanics. The presence of lymphocytic infiltrations and calcifications provides new insights into structural changes and mechanical stress in the FT, contributing to our understanding of TCS pathology.
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Meningioma is the most common intracranial neoplasm, yet there is no effective therapy for recurrent/refractory meningiomas after surgery and radiation. Prostate-specific membrane antigen (PSMA) is an enzyme upregulated on endothelial cells of multiple neoplasms and is being investigated as a theranostic target. Until now, PSMA has not been studied in meningiomas. We aimed to verify PSMA endothelial expression in meningiomas, detect tumor grade variability, and investigate the relationship of PSMA signal with tumor recurrence. We analyzed 96 archival meningiomas including 58 de novo and 38 recurrent specimens. All specimens were stained routinely and immunostained for CD31 and PSMA. Slides were scanned and analyzed producing raw data for images of PSMA, CD31, PSMA/CD31, and PSMA/vasculature. PSMA expression was seen within 98.9% of meningioma samples. In the total cohort, higher-grade tumors had increased expression of raw PSMA and PSMA/CD31, and PSMA/vasculature ratios compared to grade 1 tumors. PSMA expression and PSMA/vasculature ratios (p = 0.0015) were higher in recurrent versus de novo tumors among paired samples. ROC curves demonstrated PSMA/CD31, PSMA/vasculature, and raw CD31 as indicators of tumor recurrence. Thus, PSMA is expressed within endothelial cells of meningiomas, is increased with tumor grade and recurrence, and persists with prior irradiation.
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Neoplasias Meníngeas , Meningioma , Humanos , Masculino , Meningioma/cirugía , Recurrencia Local de Neoplasia , Medicina de Precisión , Células Endoteliales , Próstata , Neoplasias Meníngeas/cirugíaRESUMEN
BACKGROUND: Neural components of the fibrous filum terminale (FT) are well known but are considered as embryonic remnants without functionality. OBJECTIVE: To investigate the ultrastructure of human FT specimens for sensory nerve endings and record paraspinal muscle activity on electrostimulation of the FT. METHODS: We prospectively investigated a cohort of 53 patients who underwent excision of the FT for the treatment of tethered cord syndrome. Surgical FT specimens were investigated by light and transmission electron microscopy. Intraoperative electrophysiological routine monitoring was extended by recording paraspinal muscles above and below the laminotomy level. RESULTS: Light microscopy revealed tiny peripheral nerves piercing the pia mater of the FT and entering its fibrous core. Transmission electron microscopy unveiled within the fibrous core of the FT myelinated nerve structures in 8 of the 53 patients and unmyelinated ones in 10 of the 53 patients. Both nerve endings encapsulated in fibrous tissue or unencapsulated nonmyelinated Schwann cell nerve bundles, that is, Remak cells, were found. Those nerve endings resembled mechanoreceptor and nociceptive receptor structures found in human skin, muscle tendons, and skeletal ligaments. Specifically, we found Ruffini mechanoreceptors and in addition nerve endings which resembled nociceptive glioneural structures of the skin. Bipolar electrostimulation of the FT was associated with paraspinal muscle activity above and below the spinal segment at which the FT was stimulated. CONCLUSION: Morphological and electrophysiological results indicate the presence of functional sensory nerve endings in the FT. Like other spine ligaments, the FT may serve as a proprioceptive element but may also contribute to back pain in spine disorders.
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Cauda Equina , Estimulación Eléctrica , Humanos , Terminaciones Nerviosas/ultraestructura , Nocicepción , Músculos ParaespinalesRESUMEN
BACKGROUND: Patients with hypermobile Ehlers-Danlos syndrome (hEDS), a heritable connective tissue disorder, present frequently with symptoms of tethered cord syndrome (TCS) but without a low-lying conus. Currently, surgical treatment of such cases is controversial. Because connective tissue disorder affects fibrous structures, we hypothesized that a diseased filum terminale (FT) might cause TCS in hEDS, justifying surgical transection for treatment. METHODS: We investigated FT pathology, FT biomechanics, clinical presentation, and outcome following FT excision in 78 radiologically occult hEDS-TCS cases and for comparison in 38 typical TCS cases with low-lying conus and/or fatty FT infiltration but without hEDS. RESULTS: In hEDS-TCS, electron microscopy revealed inherited collagen fibril abnormalities and acquired fibril damage. Biomechanical tension tests revealed elastic properties of the FT in both study groups, but they were impaired in the hEDS TCS. Follow-up examinations at 3 and 12 months after FT excision showed statistically significant improvement of urinary, bowel, and neurologic symptoms in both study groups; intergroup comparison revealed no differences in outcome except more pronounced neurologic improvement in the hEDS-TCS group. CONCLUSIONS: Both morphologic findings and biomechanical tests indicate limited elastic properties of the FT in hEDS, which is no more able to dampen but still transmitting spine movement-related stretch forces. That mechanism exposes the conus medullaris to unphysiologic stretch forces, causing TCS, especially when considering the hypermobile spine in hEDS. This notion is supported by the observed clinical improvement following FT resection in hEDS-TCS cases without a low-lying conus.
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Cauda Equina , Síndrome de Ehlers-Danlos , Defectos del Tubo Neural , Fenómenos Biomecánicos , Cauda Equina/diagnóstico por imagen , Cauda Equina/patología , Cauda Equina/cirugía , Síndrome de Ehlers-Danlos/complicaciones , Síndrome de Ehlers-Danlos/cirugía , Humanos , Defectos del Tubo Neural/diagnóstico por imagen , Defectos del Tubo Neural/etiología , Defectos del Tubo Neural/cirugíaRESUMEN
BACKGROUND: Mucormycosis can lead to fatal rhinocerebral infection. CASE: A 53-year-old male with diabetes presented with altered mental status. He had been recently discharged from an admission for COVID-19 pneumonia treated with remdesivir and methylprednisolone. Imaging demonstrated a large left frontal mass with midline shift suspicious for a primary brain neoplasm. His neurologic exam rapidly declined and the patient was taken to the operating room for decompressive hemicraniectomy. Post-operatively, the patient remained comatose and failed to improve. Autopsy revealed a cerebral mucormycosis infection. DISCUSSION: Despite concern for a primary brain neoplasm the patient was diagnosed postmortem with a mucormycosis infection. Other features supporting this diagnosis included nasal sinusitis on initial scans, his fulminant clinical decline, rapidly progressive imaging findings, and persistent hyperglycemia throughout his clinical course. CONCLUSION: In an era of high steroid usage to treat COVID-19, mucormycosis infection must be considered in high-risk patients demonstrating disproportionate clinical decline.
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Encefalopatías , COVID-19 , Mucormicosis , Sinusitis , Encefalopatías/diagnóstico , Encefalopatías/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Mucormicosis/diagnóstico , Mucormicosis/tratamiento farmacológico , SARS-CoV-2RESUMEN
Purpose: Epithelioid glioblastoma is an unusual histologic variant of malignant glioma. The present study investigates both the genomic and transcriptomic determinants that may promote the development of this tumor. Methods: Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on an epithelioid glioblastoma, along with a specific bioinformatic pipeline to generate electronic karyotyping and investigate the tumor immune microenvironment. Microdissected sections containing typical glioblastoma features and epithelioid morphology were analyzed separately using the same methodologies. Results: An epithelioid glioblastoma, with immunopositivity for GFAP, Olig-2, and ATRX but negative for IDH-1 and p53, was identified. The tumor cell content from microdissection was estimated to be 85-90% for both histologic tumor components. WES revealed that both glioma and epithelioid sections contained identical point mutations in PTEN, RB1, TERT promoter, and TP53. Electronic karyotype analysis also revealed similar chromosomal copy number alterations, but the epithelioid component showed additional abnormalities that were not found in the glioblastoma component. The tumor immune microenvironments were strikingly different and WTS revealed high levels of transcripts from myeloid cells as well as M1 and M2 macrophages in the glioma section, while transcripts from CD4+ lymphocytes and NK cells predominated in the epithelioid section. Conclusion: Epithelioid glioblastoma may be genomically more unstable and oncogenically more advanced, harboring an increased number of mutations and karyotype abnormalities, compared to typical glioblastomas. The tumor immune microenvironment is also different.
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OBJECTIVE: The craniocervical junction (CCJ) is anatomically complex and comprises multiple joints that allow for wide head and neck movements. The thecal sac must adjust to such movements. Accordingly, the thecal sac is not rigidly attached to the bony spinal canal but instead tethered by fibrous suspension ligaments, including myodural bridges (MDBs). The authors hypothesized that pathological spinal cord motion is due to the laxity of such suspension bands in patients with connective tissue disorders, e.g., hypermobile Ehlers-Danlos syndrome (EDS). METHODS: The ultrastructure of MDBs that were intraoperatively harvested from patients with Chiari malformation was investigated with transmission electron microscopy, and 8 patients with EDS were compared with 8 patients without EDS. MRI was used to exclude patients with EDS and craniocervical instability (CCI). Real-time ultrasound was used to compare the spinal cord at C1-2 of 20 patients with EDS with those of 18 healthy control participants. RESULTS: The ultrastructural damage of the collagen fibrils of the MDBs was distinct in patients with EDS, indicating a pathological mechanical laxity. In patients with EDS, ultrasound revealed increased cardiac pulsatory motion and irregular displacement of the spinal cord during head movements. CONCLUSIONS: Laxity of spinal cord suspension ligaments and the associated spinal cord motion disorder are possible pathogenic factors for chronic neck pain and headache in patients with EDS but without radiologically proven CCI.
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The objectives of this study were to describe the anatomy, histology, and ultrastructure of the equine filum terminale (FT) and to describe the FT in hereditary equine regional dermal asthenia (HERDA), a model of human Ehlers-Danlos syndromes (EDS). Those humans suffer from tethered cord syndrome (TCS) caused by an abnormally structured FT wherein its attachment at the base of the vertebral column leads to long-term stretch-induced injury to the spinal cord. The pathophysiology of TCS in EDS is poorly understood, and there is a need for an animal model of the condition. Histopathologic and ultrastructural examinations were performed on FT from HERDA (n = 4) and control horses (n = 5) and were compared to FT from human TCS patients with and without EDS. Adipose, fibrous tissue, and neuronal elements were assessed. CD3 and CD20 immunohistochemistry was performed to clarify cell types (HERDA n = 2; control n = 5). Collagen fibrils were assessed in cross-section for fibril diameter and shape, and in longitudinal section for fibril disorganization, swelling, and fragmentation. The equine and human FT were similar, with both containing fibrous tissue, ependyma, neuropil, and nerve twigs. Hypervascularity was observed in both HERDA horses and human EDS-TCS patients and was not observed in equine or human controls. Moderate to severe abnormalities in collagen fibril orientation and architecture were observed in all HERDA horses and were similar to those observed in human EDS-TCS patients.
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Cauda Equina , Síndrome de Ehlers-Danlos , Enfermedades de los Caballos , Animales , Astenia/veterinaria , Síndrome de Ehlers-Danlos/veterinaria , Caballos , Humanos , PielRESUMEN
Mixed invasive mold infections (MIMIs) are considered rare. We present a case of fatal aspergillosis and mucormycosis in an elderly host with history of chronic lymphocytic leukemia (CLL) and potential mold exposures. Notably, he had no classic risk factors for IMI other than high-dose corticosteroids, which may be an important risk factor for (M)IMI, based on the current and previous reports. There is an urgent need for studies on the "net state of immunosuppression," environmental exposure as risk factors for (M)IMIs, and noninvasive fungal diagnostics.
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OBJECTIVE: Perineural cysts are a benign spine pathology but, when they become symptomatic and require surgical treatment, represent a significant challenge to the spine surgeon. Here we describe our experience with a novel endoscopic approach to the biopsy, drainage, resection of the cyst wall, and direct cyst fenestration to the subarachnoid space. METHODS: A transforaminal endoscopic approach to a large lumbar 2-3 perineural cyst is presented here in a 25-year-old patient. A step-by-step technique for the biopsy, drainage, and resection of the cyst wall is presented. RESULTS: The patient underwent cyst resection and fenestration into the subarachnoid space without complication, with immediate relief of his preoperative symptoms and after 1 year remains symptom-free. CONCLUSIONS: Surgical treatment of perineural cysts in the spine represent a significant challenge to the surgeon, principally due to the risk of spinal fluid leak in the postoperative period. Transforaminal endoscopic surgical access to this disease pathology is a novel minimally invasive surgical approach presented here that allows diagnosis and treatment of a perineural cyst and can be performed in an awake patient.
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Endoscopía/métodos , Procedimientos Neuroquirúrgicos/métodos , Quistes de Tarlov/diagnóstico por imagen , Quistes de Tarlov/cirugía , Adulto , Biopsia/métodos , Humanos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/patología , Imagen por Resonancia Magnética , Masculino , Mielografía , Quistes de Tarlov/patología , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Hypoxic-ischemic (HI) brain injury is one of the most common neurological problems occurring in the perinatal period. Hypothermia is the only approved intervention for neonatal HI encephalopathy. However, this treatment is only partially protective, has a narrow therapeutic time window after birth and only can be used to treat full-term infants. Consequently, additional therapies are critically needed. Inflammation is an important contributing factor to the evolution of HI brain injury in neonates. Inter-alpha Inhibitor Proteins (IAIPs) are immunomodulatory proteins with anti-inflammatory properties. We have previously shown that IAIPs reduce neuronal cell death and improve behavioral outcomes when given after carotid artery ligation, but before hypoxia in male neonatal rats. The objective of the current study was to investigate the neuroprotective effects of treatment with IAIPs given immediately or 6â¯h after HI in both male and female neonatal rats. HI was induced with the Rice-Vannucci method in postnatal (P) day 7 rats. After ligation of the right common carotid artery, P7 rats were exposed to 90â¯min of hypoxia (8% oxygen). Human plasma-derived IAIPs or placebo (phosphate buffered saline) was given at zero, 24, and 48â¯h after HI. Brains were perfused, weighed and fixed 72â¯h after HI at P10. In a second, delayed treatment group, the same procedure was followed except that IAIPs or placebo were given at 6, 24 and 48â¯h after HI. Separate sham-operated, placebo-treated groups were exposed to identical protocols but were not exposed to carotid artery ligation and remained in room air. Rat sex was recorded. The effects of IAIPs on HI brain injury were examined using histopathological scoring and immunohistochemical analyses of the brain and by using infarct volume measurements on frozen tissue of the entire brain hemispheres ipsilateral and contralateral to HI injury. IAIPs given immediately after HI improved (Pâ¯<â¯0.050) histopathological brain injury across and within the cingulate, caudate/putamen, thalamus, hippocampus and parietal cortex in males, but not in females. In contrast, IAIPs given immediately after HI reduced (Pâ¯<â¯0.050) infarct volumes of the hemispheres ipsilateral to HI injury in similarly both the males and females. Treatment with IAIPs also resulted in higher (Pâ¯<â¯0.050) brain weights compared with the placebo-treated HI group, reduced (Pâ¯<â¯0.050) neuronal and non-neuronal cell death in the cortex and total hemisphere, and also increased the total area of oligodendrocytes determined by CNPase in the ipsilateral hemisphere and corpus callosum (Pâ¯<â¯0.050) of male, but not female subjects exposed to HI. Delayed treatment with IAIPs 6â¯h after HI did not improve histopathological brain injury in males or females, but resulted in higher (Pâ¯<â¯0.050) brain weights compared with the placebo-treated HI males. Therefore, treatment with IAIPs immediately after HI improved brain weights and reduced neuropathological brain injury and cell death in male rats, and reduced infarct volume in both male and female neonatal rats. We conclude that IAIPs exert neuroprotective effects after exposure to HI in neonatal rats and may exhibit some sex-related differential effects.
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alfa-Globulinas/farmacología , Hipoxia-Isquemia Encefálica/patología , Fármacos Neuroprotectores/farmacología , Animales , Animales Recién Nacidos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Femenino , Humanos , Masculino , Ratas , Ratas WistarRESUMEN
BACKGROUND: Gastrointestinal (GI) symptoms are common in Parkinson disease (PD), often preceding neurological manifestations; however, early diagnostic utility of GI biopsies remains controversial. Studies suggest aberrant deposition of alpha-synuclein (α-syn) follows step-wise progression in central nervous system though histologic interpretation of normal and aberrant staining patterns have shown variable results. This study examines whether GI α-syn mRNA expression combined with standard α-syn immunohistochemical staining enhance the role of GI biopsy in PD. MATERIALS AND METHODS: Four groups were examined, including pediatric (21) and adult control patients (18), PD clinic patients (17), and pathologically confirmed PD cases from hospital archives (16). Enteric nervous system α-syn staining was evaluated by immunohistochemistry in 33 PD and 39 controls. α-Syn mRNA levels were compared between patient groups using quantitative polymerase chain reaction and stomach and colon levels in PD. RESULTS: PD patients had Lewy bodies (LB) and diffuse neuronal α-syn staining. GI tissues from elderly controls, children, and young adults exhibited diffuse positivity. LB were limited to PD. Myenteric plexus immunoreactivity varied in different regions. Widespread staining was noted within stomach and colon. Immunoreactivity was present within esophagus, appendix, and small bowel. α-Syn mRNA expression was highest in PD; however, levels varied between proximal and distal GI tract. CONCLUSIONS: α-Syn is normally present within young and elderly enteric nervous system; furthermore, while α-syn mRNA is always detectable, levels are highest and most variable in PD. This suggests that enteric α-syn may be altered in neurodegenerative disease. The presence of LB in the GI tract, not solely α-syn expression, may prove useful, distinguishing neurodegenerative disease patients from normal controls.
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Sistema Nervioso Entérico , Tracto Gastrointestinal , Regulación de la Expresión Génica , Enfermedad de Parkinson , alfa-Sinucleína/biosíntesis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Sistema Nervioso Entérico/metabolismo , Sistema Nervioso Entérico/patología , Femenino , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/patología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patologíaRESUMEN
BACKGROUND: In Alzheimer's disease, there are striking changes in CSF composition that relate to altered choroid plexus (CP) function. Studying CP tissue gene expression at the blood-cerebrospinal fluid barrier could provide further insight into the epithelial and stromal responses to neurodegenerative disease states. METHODS: Transcriptome-wide Affymetrix microarrays were used to determine disease-related changes in gene expression in human CP. RNA from post-mortem samples of the entire lateral ventricular choroid plexus was extracted from 6 healthy controls (Ctrl), 7 patients with advanced (Braak and Braak stage III-VI) Alzheimer's disease (AD), 4 with frontotemporal dementia (FTD) and 3 with Huntington's disease (HuD). Statistics and agglomerative clustering were accomplished with MathWorks, MatLab; and gene set annotations by comparing input sets to GeneGo ( http://www.genego.com ) and Ingenuity ( http://www.ingenuity.com ) pathway sets. Bonferroni-corrected hypergeometric p-values of < 0.1 were considered a significant overlap between sets. RESULTS: Pronounced differences in gene expression occurred in CP of advanced AD patients vs. Ctrls. Metabolic and immune-related pathways including acute phase response, cytokine, cell adhesion, interferons, and JAK-STAT as well as mTOR were significantly enriched among the genes upregulated. Methionine degradation, claudin-5 and protein translation genes were downregulated. Many gene expression changes in AD patients were observed in FTD and HuD (e.g., claudin-5, tight junction downregulation), but there were significant differences between the disease groups. In AD and HuD (but not FTD), several neuroimmune-modulating interferons were significantly enriched (e.g., in AD: IFI-TM1, IFN-AR1, IFN-AR2, and IFN-GR2). AD-associated expression changes, but not those in HuD and FTD, were enriched for upregulation of VEGF signaling and immune response proteins, e.g., interleukins. HuD and FTD patients distinctively displayed upregulated cadherin-mediated adhesion. CONCLUSIONS: Our transcript data for human CP tissue provides genomic and mechanistic insight for differential expression in AD vs. FTD vs. HuD for stromal as well as epithelial components. These choroidal transcriptome characterizations elucidate immune activation, tissue functional resiliency, and CSF metabolic homeostasis. The BCSFB undergoes harmful, but also important functional and adaptive changes in neurodegenerative diseases; accordingly, the enriched JAK-STAT and mTOR pathways, respectively, likely help the CP in adaptive transcription and epithelial repair and/or replacement when harmed by neurodegeneration pathophysiology. We anticipate that these precise CP translational data will facilitate pharmacologic/transgenic therapies to alleviate dementia.