Background The recent promise of disease-modifying therapies for Alzheimer’s disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation. Methods We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer’s Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid β peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change. Results The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Aβ42/Aβ40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Aβ+ and Aβ− groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years. Conclusions This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

The wide variety of transgenic mouse models of Alzheimer's disease (AD) reflects the search for specific genes that influence AD pathology and the drive to create a clinically relevant animal model. An ideal AD mouse model must display hallmark AD pathology such as amyloid plaques, neurofibrillary tangles, reactive gliosis, dystrophic neurites, neuron and synapse loss, and brain atrophy and in parallel behaviorally mimic the cognitive decline observed in humans. Magnetic resonance (MR) microscopy (MRM) can detect amyloid plaque load, development of brain atrophy, and acute neurodegeneration. MRM examples of AD pathology will be presented and discussed. What has lagged behind in preclinical research using transgenic AD mouse models is functional phenotyping of the brain; in other words, the ability to correlate a specific genotype with potential aberrant brain activation patterns. This lack of information is caused by the technical challenges involved in performing functional MRI (fMRI) in mice including the effects of anesthetic agents and the lack of relevant "cognitive" paradigms. An alternative approach to classical fMRI using external stimuli as triggers of brain activation in rodents is to electrically or pharmacologically stimulate regions directly while simultaneously locally tracking the activated interconnected regions of rodents using, for example, the manganese-enhanced MRI (MEMRI) technique. Finally, transgenic mouse models, MRM, and future AD research would be strengthened by the ability to screen for AD-like pathology in other non-AD transgenic mouse models. For example, molecular biologists may focus on cardiac or pulmonary pathologies in transgenic mice models and as an incidental finding discover behavioral AD phenotypes. We will present MRM data of brain and cardiac phenotyping in transgenic mouse models with behavioral deficits.

Schizophrenia is a complex constellation of positive, negative and cognitive symptoms. Acute administration of the non-competitive antagonist of the N-methyl D-aspartate receptor (NMDAR) dizocilpine (MK801) in rats is one of few preclinical animal models of this disorder that has both face and/or construct validity for these multiple at-risk behavioral domains and predictive power for the efficacy of therapeutic drugs in treating them. This study asked whether and to what extent the rat NMDAR hypofunction model also embodies the sex differences that distinguish the symptoms of schizophrenia and their treatment. Thus, we compared the effects of acute MK801, with and without pretreatment with haloperidol or clozapine, on seven discrete spontaneous open field activities in adult male and female rats. These analyses revealed that MK801 was more effective in stimulating ataxia and locomotion and inhibiting stationary behavior in females while more potently stimulating stereotypy and thigmotaxis and inhibiting rearing and grooming in males. Haloperidol and clozapine pretreatments had markedly different efficacies in terms of behaviors but strong similarities in their effectiveness in male and female subjects. These results bear intriguing relationships with the complex male/female differences that characterize the symptoms of schizophrenia and suggest possible applications for acute NMDAR hypofunction as a preclinical model for investigating the neurobiology that underlies them.

Major surgery is often complicated by postoperative neurocognitive disorder. Affected patients exhibit problems with memory and executive function, similar to deficits seen in Alzheimer disease (AD). 1,2 A critical question is whether surgery can exacerbate or unmask latent pathophysiology underlying the development of AD. 2 Plasma biomarkers of neuronal damage including total tau and neurofilament light chain (NfL) suggest that surgery can trigger injury. 3 Unlike total tau and NfL levels that increase in different brain disorders, the plasma level of tau protein phosphorylated at threonine residue 181 (pTau181) is relatively specific and predictive of AD. 4 Whether major surgery triggers increases in plasma pTau181 is unknown.Lowest core temperature, °C 35.5 (35.0-35.9) 28.1 (28.0-35.3) Cardiopulmonary bypass duration, min NA 183 (63-512) Circulatory arrest NA 3 Yes, 3 no Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); NA, not applicable.

Background: Pheochromocytoma is a rare medical condition caused by catecholamine-secreting tumor cells. Operative resection can be associated with significant hemodynamic fluctuations due to the nature of the tumor, as well as associated post-resection vasoplegia. To allow for cardiovascular recovery before surgery, patients require pre-operative alpha-adrenergic blockade, which would be limited in the setting of co-existent severe aortic stenosis. In this report, we describe a patient with severe aortic stenosis and symptomatic pheochromocytoma. Case presentation: A 51-year-old man with severe aortic stenosis (valve area 0.8 cm2) was found to have a highly active 4x4 cm left adrenal pheochromocytoma. Alpha-adrenergic blockade for his pheochromocytoma was limited by syncope in the setting of his aortic stenosis. Open aortic valve replacement (AVR) was performed, followed by adrenalectomy the next day. The perioperative course for each surgical procedure was hemodynamically volatile, exacerbated by severe alcohol withdrawal. During the adrenalectomy, cardiogenic and vasoplegic shock developed immediately after securing the vascular supply to his tumor. This shock was refractory to vasopressin and methylene blue, but responded well to angiotensin II and epinephrine. After both surgeries were completed, his course was further complicated by severe ICU psychosis, ileus, fungal bacteremia, pneumonia/hypoxic respiratory failure and atrial fibrillation. He ultimately recovered and was discharged from the hospital after 38 days. Conclusion: To our knowledge, this is the first report of surgical AVR and pheochromocytoma resection in a patient with critical aortic stenosis. The appropriate order and timing of surgeries when both these conditions co-exist remains controversial.