Total Tau Level in Cerebrospinal Fluid as a Predictor of Survival in Creutzfeldt-Jakob Disease: A Retrospective Analysis.

Background and Objectives: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and universally fatal neurodegenerative disorder with highly variable survival times, ranging from weeks to years. However, there are currently no tools for prognosticating a patient's survival time. This study aims to fill this gap by examining the relationship between CSF total tau (t-tau) levels and time to death in patients with CJD. Methods: We use cases with CJD recorded in the electronic health record of a tertiary academic medical center from 2010 to 2022. Results: We identified 29 cases with diagnosis of CJD. Using a Cox proportional hazards model, we find that elevated t-tau levels (>4,000 pg/mL) are associated with 9.62 (95% confidence interval: 1.93-47.92) times the hazard of death compared with CJD patients with t-tau less than 4,000 pg/mL. Discussion: This finding supports the use of CSF t-tau as a prognostic biomarker for CJD.

The Tragedy of a Strong Muscle and a Weak Heart: Complications of Anabolic-Androgenic Steroid Misuse.

Misuse of anabolic-androgenic steroids (AAS) to boost performance and appearance is rising in the United States (US) with approximately one million people experiencing dependence. Long-term AAS misuse can lead to cardiovascular pathology but rarely cardiogenic shock. We report the case of an acute ischemic stroke secondary to an intracardiac thrombus in a patient with biventricular failure and cardiogenic shock associated with AAS misuse. Discontinuation of AAS and institution of guideline-directed medical therapy might reverse AAS-related heart failure.

Real-world experience of ocrelizumab initiation in a diverse multiple sclerosis population.

BACKGROUND: Ocrelizumab (OCR) is a humanized monoclonal antibody directed against CD20 positive B-lymphocytes. It was approved for use in 2017 by the U.S. Food and Drug Administration (FDA) for both the relapsing-remitting and primary progressive forms of multiple sclerosis (MS). OBJECTIVE: To provide real-world data for patients with MS treated with OCR in our center and evaluate both the safety and efficacy across different ethnic groups not studied in previous clinical trials. METHODS: We performed a retrospective observational analysis of MS patients who were treated with OCR from March 31, 2017 to April 30, 2020. We collected data on patients who had received at least a one dose infusion of OCR at our MS center. Patient characteristics, including demographics, clinical disease course, and documented side effects, were collected and analyzed. RESULTS: A total of 82 patients were eligible for this study, of which 72% had relapsing-remitting MS (RRMS), 14% had primary progressive MS (PPMS), and 11% active/relapsing secondary progressive MS (SPMS). 22% of our patients were of African American descent, 61% Caucasian, and 17% of Hispanic descent. The mean age of starting OCR was 41 ± 11 years. 47% were treatment naïve when started on OCR, 24% were previously treated with one disease-modifying therapy (DMT), 14% were treated with two DMTs, and 15% were treated with more than two DMTs prior to OCR. 50% of patients had at least one adverse event while on OCR; 4.8% had adverse events requiring to OCR discontinuation, 36% had infusion-related reactions, and 7.3% had viral infections. We found two cases of severe babesiosis along with index cases of re-activation of lichen planus, agranulocytosis, severe lymphopenia, and ectopic pregnancy. There were no cases of malignancy, progressive multifocal leukoencephalopathy, or death within our cohort. The mean time after OCR initiation was 17.3 months in the RRMS group, 22.2 months in the PPMS group, and 28.2 months in SPMS group. The annualized relapse rate reduced from 1.33 to 0.15 in the RRMS group. The mean extended disability status scale (EDSS) scores did not worsen across MS phenotypes and ethnic groups while being treated with OCR. CONCLUSIONS: In a diverse patient population, OCR was well-tolerated without significant adverse events. There were novel cases of severe babesiosis, re-activation of lichen planus, lymphopenia, agranulocytosis, and ectopic pregnancy. It is vital to consider geographic risk factors that may expose patients to Babesia microti (B. microti) when either considering or initiating OCR therapy. There were an additional six cases of severe B. microti cases associated with OCR that were reported to the FDA adverse event reporting system (FAERS) along with multiple babesiosis cases associated with other DMTs, including rituximab. OCR was found in our cohort to be effective by decreasing relapse rates and maintaining EDSS scores. Our study extends the generalizability of OCR from clinical trials to a real-world setting consisting of a diverse population.

Babesia microti infection in a patient with multiple sclerosis treated with ocrelizumab.

Ocrelizumab is a humanized monoclonal anti-CD20 antibody approved for treatment of relapsing-remitting and primary progressive multiple sclerosis (MS). Rare parasitic infections have been reported in patients with lymphoproliferative disorders using rituximab, a chimeric anti-CD20 antibody used off-label for the treatment of MS. Here, we report a patient with MS on ocrelizumab with B-cell depletion who developed severe Babesia microti (B. microti) infection with neutropenia, hemolytic anemia, and thrombocytopenia. He recovered after prompt diagnosis and treatment. This case represents the first published occurrence of babesiosis in a patient with MS on ocrelizumab. It also adds to the accumulating evidence from databases of emergent severe or relapsing B. microti infection in patients receiving anti-CD20 antibodies. This presentation stresses the diagnostic vigilance required by MS neurologists in endemic areas to identify cases of babesiosis in patients on anti-CD20 therapy and to better counsel these individuals on their risks of B. microti infection.

Preventive neurology concepts for training the next-generation and closing gaps in real-world Multiple Sclerosis Care.

The field of Multiple sclerosis (MS) has entered an area of growth in the understanding of the MS immune dysregulation that has led to an impressive therapeutics expansion. However, results of surveys and proceedings of the American Academy of Neurology (AAN) support the notion that US neurology residents have fragmented exposure to MS training during residency, resulting in learning gaps in diagnosis, management and follow up of patients with MS. There are annual educational offerings by MS academic societies but limited and tailored to trainees interested in MS/neuroimmunology subespecialization. Therefore, the acquisition of MS clinical skills by all neurology residents is essential for the practice of unsupervised neurology after board certification. Here, we review the current elements and goals of care that are critical for the learning of trainees. We present these elements in a framework focused on current unmet needs to avoid progression in MS in a real-world setting, tailored to preventive and personalized care: The "Multiple Sclerosis 4-square Educational Matrix". This approach could help training neurologist and patients through the essential steps of care. The trainee side emphasizes a goal-oriented approach to satisfy the educational and management components of MS in four areas: burden of symptoms, burden of disease activity, personalized risk factors and personalized patient education. The patient side is similar but simplified for their benefit. This structured approach is based on the principles of personalized preventive neurology and could be useful to solidify trainees and patient education, promoting proactive participation of patients in vital areas of their care, in an anticipatory, and goal-oriented manner. We aim to improve the unmet needs at an individual level and the value of care of populations at risk for progression and disability in MS.

Effects of HIV-1 TAT protein and methamphetamine exposure on visual discrimination and executive function in mice.

Mild neurocognitive impairments are common in people with human immunodeficiency virus (HIV) infection. HIV-encoded proteins, such as trans-activator of transcription (TAT), contribute to neuropathology and cognitive function in medicated subjects. The combination of TAT and comorbid methamphetamine use may further impair neurocognitive function in HIV-positive individuals by affecting dopaminergic systems in the brain. The current study examined the effects of TAT protein expression and methamphetamine exposure on cognitive function and dopamine systems in mice. Transgenic mice with inducible brain expression of the TAT protein were exposed to a binge methamphetamine regimen. TAT expression was induced via a doxycycline-containing diet during the final stage of the regimen and maintained throughout cognitive testing. Learning and executive function were assessed using an operant visual discrimination protocol, with a strategy switch and reversal. TAT expression and methamphetamine exposure improved visual discrimination learning. Combined TAT expression and methamphetamine exposure increased perseverative errors during reversal learning. TAT expression altered reversal learning by improving early stage, but impairing late stage, learning. TAT expression was also associated with an increase in dopamine transporter expression in the caudate putamen. These results highlight that TAT expression and methamphetamine exposure likely affect a range of selective cognitive processes, with some potentially improving function under certain conditions.

Molecular Disorganization of Axons Adjacent to Human Cortical Microinfarcts.

Cortical microinfarcts (CMIs) are microscopically identified wedge-shaped ischemic lesions that occur at or near the cortical surface and result from occlusion of penetrating arterioles. These microscopic lesions can be observed with high-resolution magnetic resonance imaging in aging brains and in patients with cerebrovascular disease. Recent studies have suggested that strategically located microinfarcts strongly correlate with cognitive deficits, which can contribute to Alzheimer's disease as well as other forms of dementia. We have recently shown that the molecular organization of axons into functional microdomains is altered in areas adjacent to white matter lacunar and microinfarcts, creating a peri-infarct penumbral injury in surviving axons. Whether similar changes in nodal, adjacent paranodal, and proximal axon initial segment molecular organization occur in the cortex adjacent to human CMIs is not known. Paraffin-embedded sections of autopsy brain tissue from five patients with CMIs were immunofluorescently labeled for nodal and paranodal markers including beta-IV spectrin, ankyrin-G, and contactin-associated protein. High magnification images from the peri-infarct cortical tissue were generated using confocal microscopy. In surviving cortical tissue adjacent to microinfarcts, we observed a dramatic loss of axon initial segments, suggesting that neuronal firing capacity in adjacent cortical tissue is likely compromised. The number of identifiable nodal/paranodal complexes in surviving cortical tissue is reduced adjacent to microinfarcts, while the average paranodal length is increased indicating a breakdown of axoglial contact. This axonal microdomain disorganization occurs in the relative absence of changes in the structural integrity of myelinated axons as measured by myelin basic protein and neurofilament staining. These findings indicate that the molecular organization of surviving axons adjacent to human CMIs is abnormal, reflecting lost axoglial contact and the functional elements necessary for neural transmission. This study provides support for the concept of a microinfarct penumbral injury that may account for the cumulative cognitive effect of these tiny strokes.

Impact of aging on neurocognitive performance in previously antiretroviral-naive HIV-infected individuals on their first suppressive regimen.

BACKGROUND: Despite treatment with virologically suppressive antiretroviral therapy (ART), neurocognitive impairment may persist or develop de novo in aging HIV-infected individuals. We evaluated advancing age as a predictor of neurocognitive impairment in a large cohort of previously ART-naive individuals on long-term ART. DESIGN: The AIDS Clinical Trials Group Longitudinal Linked Randomized Trials was a prospective cohort study of HIV-infected individuals originally enrolled in randomized ART trials. This analysis examined neurocognitive outcomes at least 2 years after ART initiation. METHODS: All participants underwent annual neurocognitive testing consisting of Trail making A and B, the wechsler adult intelligence scale-revised Digit Symbol and Hopkins Verbal Learning Tests. Uni and multivariable repeated measures regression models evaluated factors associated with neurocognitive performance. Predictors at parent study entry (ART naive) included entry demographics, smoking, injection drug use, hepatitis B surface antigen, hepatitis C virus serostatus, history of stroke, ART regimen type, pre-ART nadir CD4 cell count, and plasma viral load and as well as time-updated plasma viral load and CD4 cell count. RESULTS: The cohort comprised 3313 individuals with median pre-ART age of 38 years, 20% women; 36% Black, non-Hispanic; 22% Hispanic. Virologic suppression was maintained at 91% of follow-up visits. Neurocognitive performance improved with years of ART. After adjusting for the expected effects of age using norms from HIV-negative individuals, the odds of neurocognitive impairment at follow-up visits among the HIV infected increased by nearly 20% for each decade of advancing age. CONCLUSION: Despite continued virologic suppression and neurocognitive improvement in the cohort as a whole, older individuals were more likely to have neurocognitive impairment than younger individuals.