Remote Associations Between Tau and Cortical Amyloid-ß Are Stage-Dependent.

Background: Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-ß (Aß) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. Objective: In this study, we utilized Aß and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aß deposition. Methods: Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aß associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. Results: No significant tau-Aß association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aß in lateral temporal lobe regions. The strongest tau-Aß associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aß (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aß associations were no longer significant. Conclusions: The results indicate that associations between tau and Aß are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD.

Distinct and joint effects of low and high levels of Aß and tau deposition on cortical thickness.

Alzheimer's disease (AD) is defined by the presence of Amyloid-ß (Aß),tau, and neurodegeneration (ATN framework) in the human cerebral cortex. Yet, prior studies have suggested that Aß deposition can be associated with both cortical thinning and thickening. These contradictory results are attributed to small sample sizes, the presence versus absence of tau, and limited detectability in the earliest phase of protein deposition, which may begin in young adulthood and cannot be captured in studies enrolling only older subjects. In this study, we aimed to find the distinct and joint effects of Aß andtau on neurodegeneration during the progression from normal to abnormal stages of pathologies that remain elusive. We used18F-MK6240 and 18F-Florbetaben/18F-Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI) to quantify tau, Aß, and cortical thickness in 590 participants ranging in age from 20 to 90. We performed multiple regression analyses to assess the distinct and joint effects of Aß and tau on cortical thickness using 590 healthy control (HC) and mild cognitive impairment (MCI) participants (141 young, 394 HC elderlies, 52 MCI). We showed thatin participants with normal levels of global Aßdeposition, Aß uptakewassignificantly associated with increasedcortical thickness regardless of tau (e.g., left entorhinal cortex with t > 3.241, p < 0.0013). The relationship between tau deposition and neurodegeneration was more complex: in participants with abnormal levels of global tau, tau uptake was associated with cortical thinning in several regions of the brain (e.g., left entorhinal with t < -2.80, p < 0.0096 and left insula with t-value < -4.284, p < 0.0001), as reported on prior neuroimaging and neuropathological studies. Surprisingly, in participants with normal levels of global tau, tau was found to be associated with cortical thickening. Moreover, in participants with abnormal levels of global Aßandtau, theresonancebetween them, defined as their correlation throughout the cortex, wasassociated strongly with cortical thinning even when controlling for a direct linear effect. We confirm prior findings of an association between Aß deposition and cortical thickening and suggest this may also be the case in the earliest stages of deposition in normal aging. We also illustrate that resonance between high levels of Aß and tau uptake is strongly associated with cortical thinning, emphasizing the effects of Aß/tau synergy inAD pathogenesis.

Topographical Overlapping of the Amyloid-ß and Tau Pathologies in the Default Mode Network Predicts Alzheimer's Disease with Higher Specificity.

BACKGROUND: While amyloid-ß (Aß) plaques and tau tangles are the well-recognized pathologies of Alzheimer's disease (AD), they are more often observed in healthy individuals than in AD patients. This discrepancy makes it extremely challenging to utilize these two proteinopathies as reliable biomarkers for the early detection as well as later diagnosis of AD. OBJECTIVE: We hypothesize and provide preliminary evidence that topographically overlapping Aß and tau within the default mode network (DMN) play more critical roles in the underlying pathophysiology of AD than each of the tau and/or Aß pathologies alone. METHODS: We used our newly developed quantification methods and publicly available neuroimaging data from 303 individuals to provide preliminary evidence of our hypothesis. RESULTS: We first showed that the probability of observing overlapping Aß and tau is significantly higher within than outside the DMN. We then showed evidence that using Aß and tau overlap can increase the reliability of the prediction of healthy individuals converting to mild cognitive impairment (MCI) and to a lesser degree converting from MCI to AD. Finally, we provided evidence that while the initial accumulations of Aß and tau seems to be started independently in the healthy participants, the accumulations of the two pathologies interact in the MCI and AD groups. CONCLUSION: These findings shed some light on the complex pathophysiology of AD and suggest that overlapping Aß and tau pathologies within the DMN might be a more reliable biomarker of AD for early detection and later diagnosis of the disease.

Challenges of diagnosis of COVID-19 in trauma patients: A case series.

Background: Diagnosis of COVID-19 can be challenging in trauma patients, especially those with chest trauma and lung contusion. Methods: We present a case series of patients from February and March 2020 who were admitted to our trauma center at Rajaee Hospital Trauma Center, in Shiraz, Iran and had positive SARS-CoV-2 PCR test or chest CT scan suggestive of COVID-19 and were admitted to the specific ICU for COVID-19. Results: Eight COVID-19 patients (6 male) with mean age of 40 (SD = 16.3) years old, were presented. All patients were cases of trauma injuries, with multiple injuries including chest trauma and lung contusion, admitted to our trauma center for management of their injuries, but they were diagnosed with COVID-19 as well. Two of them had coinfection of influenza type-B and SARS-CoV-2. All patients were treated for COVID-19 and three of them died; the rest were discharged from hospital. Conclusion: Since PCR for SARS-CoV-2 is not always sensitive enough to confirm the cause of pneumonia, chest CT manifestations can be helpful, though, they are not always differentiable from lung contusion. Therefore, both the CT scan and the clinical and paraclinical presentation and course of improvement can be beneficial in diagnosing COVID-19 in the trauma setting.

The complexity of eye-hand coordination: a perspective on cortico-cerebellar cooperation.

BACKGROUND: Eye-hand coordination (EHC) is a sophisticated act that requires interconnected processes governing synchronization of ocular and manual motor systems. Precise, timely and skillful movements such as reaching for and grasping small objects depend on the acquisition of high-quality visual information about the environment and simultaneous eye and hand control. Multiple areas in the brainstem and cerebellum, as well as some frontal and parietal structures, have critical roles in the control of eye movements and their coordination with the head. Although both cortex and cerebellum contribute critical elements to normal eye-hand function, differences in these contributions suggest that there may be separable deficits following injury. METHOD: As a preliminary assessment for this perspective, we compared eye and hand-movement control in a patient with cortical stroke relative to a patient with cerebellar stroke. RESULT: We found the onset of eye and hand movements to be temporally decoupled, with significant decoupling variance in the patient with cerebellar stroke. In contrast, the patient with cortical stroke displayed increased hand spatial errors and less significant temporal decoupling variance. Increased decoupling variance in the patient with cerebellar stroke was primarily due to unstable timing of rapid eye movements, saccades. CONCLUSION: These findings highlight a perspective in which facets of eye-hand dyscoordination are dependent on lesion location and may or may not cooperate to varying degrees. Broadly speaking, the results corroborate the general notion that the cerebellum is instrumental to the process of temporal prediction for eye and hand movements, while the cortex is instrumental to the process of spatial prediction, both of which are critical aspects of functional movement control.

Early, delayed, and expanded intracranial hemorrhage in cerebral venous thrombosis.

OBJECTIVES: One of the most important prognostic factors of cerebral venous sinus thrombosis (CVST) is intracranial hemorrhage (ICH). We studied the risk factors, clinical, and radiologic characteristics of early, delayed, and expanded ICH in Iranian patients with CVST. MATERIALS AND METHODS: In a retrospective study, from August 2012 to September 2016, all adult patients with a confirmed diagnosis of CVST were recruited. Demographic, clinical, and radiologic characteristics of the patients were recorded. The predictors of early, delayed, and expanded ICH were assessed through logistic regression analysis. RESULTS: Among 174 eligible patients, 35.1% of the patients had early ICH. Delayed and expanded hemorrhage occurred in 5% and 7.4% of the patients, respectively. Higher age was a risk factor (odds ratio [OR] = 1.038, 95% confidence interval [CI] = 1.008-1.069), and involvement of multiple sinuses/veins was associated with lower risk of early ICH (OR = 0.432, CI = 0.226-0.827). The risk of delayed ICH was higher in the patients with early hemorrhage (OR = 4.44, CI: 0.990-19.94), men (OR = 4.18, CI: 0.919-19.05), and those with a focal neurologic deficit on admission (OR = 16.05, CI: 1.82-141.39). Acute onset was the predictor of the expansion of early ICH (OR = 8.92, CI: 1.81-43.77), whereas female gender-related conditions were associated with a lower risk of hemorrhage expansion (OR = 0.138, CI: 0.025-0.770). Administration of anticoagulants was associated with neither delayed (P value = .140) nor expanded hemorrhage (P-value = .623). CONCLUSIONS: Male gender, early hemorrhages, acute onset, and presence of focal neurologic deficit are the risk factors for delayed and/or expanded hemorrhages in the patients with CVST.

Cost-Effectiveness Analysis of the Unfractionated Heparin versus Low-Molecular-Weight Heparin in Hospitalized Patients with Stroke Due to Atrial Fibrillation in Shiraz, South of Iran.

BACKGROUND: Patients with atrial fibrillation (AF) make a unique group of strokes. Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are among the medications used for preventing blood coagulation. This study was carried out aiming at analyzing the cost effectiveness of LMWH versus UFH in hospitalized patients with stroke due to AF with respect to the Iranian population. METHODS: This randomized study was an economic evaluation of cost effectiveness with the help of the cross-sectional data of 2013-2015. In this study, 74 patients had undergone treatment in two groups, before being evaluated. Half of the patients were treated by LMWH, while the other half was treated by UFH. Effectiveness criterion was prevention of new stroke recurrence. RESULTS: Average medical direct costs, non-medical direct costs, and indirect costs of UFH were 110375 ± 40411$, 15594 ± 11511$, and 21723 ± 19933$, respectively. Same average medical direct costs, non-medical direct costs, and indirect costs of LMWH were 99573 ± 59143$, 9016 ± 17156$, and 10385 ± 10598$, respectively. The number of prevention of new strokes due to AF in LMWH and UFH was 2 and 0, respectively. Expected effectiveness in LMWH and UFH groups was 0.56 and 0.51, respectively. Moreover, the expected costs were 26737.61$ and 30776.18$, respectively. The incremental cost-effectiveness ratio for stroke due to AF was -150, 201, 26$ per prevention of stroke recurrence (p-values ≤ 0/05). CONCLUSION: The results of the cost-effectiveness analysis of LMWH versus UFH showed that LMWH is a dominant strategy for patients with stroke due to AF in Iranian population.

Study of the Efficacy, Safety and Tolerability of Low-Molecular-Weight Heparin vs. Unfractionated Heparin as Bridging Therapy in Patients with Embolic Stroke due to Atrial Fibrillation.

BACKGROUND: Anticoagulation with adjusted dose warfarin is a well-accepted treatment for the prevention of recurrent stroke in patients with atrial fibrillation. Meanwhile, using bridging therapy with heparin or heparinoids before warfarin for initiation of anticoagulation is a matter of debate. We compared safety, efficacy, and tolerability of low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) as a bridging method in patients with recent ischemic stroke due to atrial fibrillation. METHOD: This study was a randomized single-blind controlled trial in patients with acute ischemic stroke due to atrial fibrillation who were eligible for receiving warfarin and were randomly treated with 60 milligrams (mg) of LMWH (enoxaparin) subcutaneously every 12 h, or 1000 units/h of continuous intravenous heparin. The primary efficacy endpoints were recurrence of new ischemic stroke, myocardial infarction and/or death. The primary safety endpoint was central nervous system and/or systemic bleeding. RESULTS: Seventy-four subjects were recruited. Baseline demographic and clinical characteristics of two groups were matched. Composite endpoint outcome of new ischemic stroke, myocardial infarction, and/or death in follow-up period was seen in 10 subjects (27.03%) in UFH group and in four subjects (10.81%) in LMWH group (p value: 0.136). All hemorrhages and symptomatic central nervous system (CNS) hemorrhages in follow-up period were in 7 (18.9%) and 4 (10.8%) patients in UFH group, in 5 (13.5%), and 3 (8.1%) patients in LMWH group (p values: 0.754 and 0.751), respectively. Drop out and major adverse-effects such as heparin-induced thrombocytopenia and drug hypersensitivity were not seen in any patient. CONCLUSION: Enoxaparin can be a safe and efficient alternative for UFH as bridging therapy.