Deep Parasternal Intercostal Plane Block for Postoperative Analgesia After Sternotomy for Cardiac Surgery-A Retrospective Cohort Study.

OBJECTIVE: To examine the analgesic efficacy of postoperative deep parasternal intercostal plane (DPIP) blocks for patients having cardiac surgery via median sternotomy. DESIGN: This single-center retrospective study compared patients receiving bilateral DPIP blocks with a matched cohort of patients not receiving DPIP blocks. SETTING: Large quaternary referral center. PARTICIPANTS: Adult patients admitted to the authors' institution from January 1, 2016, to August 14, 2020, for elective cardiac surgery via median sternotomy. INTERVENTIONS: Patients received ultrasound-guided bilateral DPIP blocks. MEASUREMENTS AND MAIN RESULTS: A total of 113 patients received a DPIP block; 3,461 patients did not. The estimated multiplicative change in cumulative opioid consumption through 24 hours was 0.42 (95% CI 0.32-0.56; p < 0.001), indicating that patients receiving DPIP blocks required 60% fewer opioids than patients who did not. Proportional odds ratios for the average pain score on postoperative day (POD) 0 was 0.46 (95% CI 0.32-0.65; p < 0.001), and POD 1 was 0.67 (95% CI 0.47-0.94; p = 0.021), indicating lower pain scores for patients receiving blocks. The exploratory analysis identified an inverse correlation between DPIP blocks and atrial fibrillation incidence (2% v 15%; inverse probability of treatment weighting odds ratio 0.088, 95% CI 0.02-0.41; p = 0.002). CONCLUSIONS: The use of DPIP blocks in patients undergoing cardiac surgery via median sternotomy was associated with less opioid use and improved pain scores in the early postoperative period compared with patients not receiving blocks. Prospective randomized controlled studies should further elucidate the efficacy and risks of DPIP blocks in cardiac surgery.

Pectoral Fascial Plane Versus Paravertebral Blocks for Minimally Invasive Mitral Valve Surgery Analgesia.

OBJECTIVES: This study examined the postoperative analgesic efficacy of single-injection pectoral fascial plane (PECS) II blocks compared to paravertebral blocks for elective robotic mitral valve surgery. DESIGN: A single-center retrospective study that reported patient and procedural characteristics, postoperative pain scores, and postoperative opioid use for patients undergoing robotic mitral valve surgery. SETTING: This investigation was performed at a large quaternary referral center. PARTICIPANTS: Adult patients (age ≥18) admitted to the authors' hospital from January 1, 2016, to August 14, 2020, for elective robotic mitral valve repair who received either a paravertebral or PECS II block for postoperative analgesia. INTERVENTIONS: Patients received an ultrasound-guided, unilateral paravertebral or PECS II nerve block. MEASUREMENTS AND MAIN RESULTS: One hundred twenty-three patients received a PECS II block, and 190 patients received a paravertebral block during the study period. The primary outcome measures were average postoperative pain scores and cumulative opioid use. Secondary outcomes included hospital and intensive care unit lengths of stay, need for reoperation, need for antiemetics, surgical wound infection, and atrial fibrillation incidence. Patients receiving the PECS II block required significantly fewer opioids in the immediate postoperative period than the paravertebral block group, and had comparable postoperative pain scores. No increase in adverse outcomes was noted for either group. CONCLUSIONS: The PECS II block is a safe and highly effective option for regional analgesia for robotic mitral valve surgery, with demonstrated efficacy comparable to the paravertebral block.

Perioperative Outcomes for Radical Nephrectomy and Level III-IV Inferior Vena Cava Tumor Thrombectomy in Patients with Renal Cell Carcinoma.

OBJECTIVES: This study examined the characteristics, intraoperative, and postoperative course of patients undergoing inferior vena cava tumor thrombectomy for metastatic renal cell carcinoma. DESIGN: A single-center case series that reported demographic data and intraoperative and postoperative outcomes for patients with renal cell carcinoma undergoing inferior vena cava thrombectomy. SETTING: This investigation was performed at a large quaternary referral center. PARTICIPANTS: Adult patients (age ≥18) admitted to the authors' hospital from January 1, 2005, to March 10, 2017, undergoing inferior vena cava thrombectomy for level III and IV renal cell carcinoma. INTERVENTIONS: No interventions were performed. MEASUREMENTS AND MAIN RESULTS: Sixty-five patients who met the inclusion criteria were identified, with 31 patients diagnosed with level III and 34 with level IV renal cell carcinoma. Patients with level IV tumors were significantly more likely to have greater intraoperative blood loss, had longer surgical duration and hospital stays, and had more frequently required blood products, pressors, and cardiopulmonary bypass intraoperatively. Intraoperative transesophageal echo was more frequently used in level IV thrombectomy compared to level III (91.2% v 67.7%). Of patients with level IV thrombus, 41.2% developed postoperative atrial fibrillation compared to only 3.2% with level III thrombus. The 30-day mortality was 4.6% for both groups. CONCLUSIONS: Patients undergoing inferior vena cava tumor thrombectomy for renal cell carcinoma had more complex intraoperative and postoperative courses with level IV compared to level III tumor thrombus.

Baseline Microglial Activation Correlates With Brain Amyloidosis and Longitudinal Cognitive Decline in Alzheimer Disease.

BACKGROUND AND OBJECTIVES: This study aims to quantify microglial activation in individuals with Alzheimer disease (AD) using the 18-kDa translocator protein (TSPO) PET imaging in the hippocampus and precuneus, the 2 AD-vulnerable regions, and to evaluate the association of baseline neuroinflammation with amyloidosis, tau, and longitudinal cognitive decline. METHODS: Twenty-four participants from the Knight Alzheimer Disease Research Center (Knight ADRC) were enrolled and classified into stable cognitively normal, progressor, and symptomatic AD groups based on clinical dementia rating (CDR) at 2 or more clinical assessments. The baseline TSPO radiotracer [11C]PK11195 was used to image microglial activation. Baseline CSF concentrations of Aß42, Aß42/Aß40 ratio, tau phosphorylated at position 181 (p-tau181), and total tau (t-tau) were measured. Clinical and cognitive decline were examined with longitudinal CDR and cognitive composite scores (Global and Knight ADRC-Preclinical Alzheimer Cognitive Composite [Knight ADRC-PACC] Score). RESULTS: Participants in the progressor and symptomatic AD groups had significantly elevated [11C]PK11195 standard uptake value ratios (SUVRs) in the hippocampus but not in the precuneus region. In the subcohort with CSF biomarkers (16 of the 24), significant negative correlations between CSF Aß42 or Aß42/Aß40 and [11C]PK11195 SUVR were observed in the hippocampus and precuneus. No correlations were observed between [11C]PK11195 SUVR and CSF p-tau181 or t-tau at baseline in those regions. Higher baseline [11C]PK11195 SUVR averaged in the whole cortical regions predicted longitudinal decline on cognitive tests. DISCUSSION: Microglial activation is increased in individuals with brain amyloidosis and predicts worsening cognition in AD. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with AD, higher baseline [11C]PK11195 SUVR averaged in the whole cortical regions was associated with longitudinal decline on cognitive tests.

A Blinded Randomized Trial Comparing Standard Activated Clotting Time Heparin Management to High Target Active Clotting Time and Individualized Hepcon HMS Heparin Management in Cardiopulmonary Bypass Cardiac Surgical Patients.

PURPOSE: High-dose heparin has been suggested to reduce consumption coagulopathy. MATERIALS AND METHODS: In a randomized, blinded, prospective trial of patients undergoing elective, complex cardiac surgery with cardiopulmonary bypass, patients were randomized to one of three groups: 1) high-dose heparin (HH) receiving an initial heparin dose of 450 u/kg, 2) heparin concentration monitoring (HC) with Hepcon Hemostasis Management System (HMS; Medtronic, Minneapolis, MN, USA) monitoring, or 3) a control group (C) receiving a standard heparin dose of 300 u/kg. Primary outcome measures were blood loss and transfusion requirements. RESULTS: There were 269 patients block randomized based on primary versus redo sternotomy to one of the three groups from August 2001 to August 2003. There was no difference in operative bleeding between the groups. Chest tube drainage did not differ between treatment groups at 8 hours (median [25th percentile, 75th percentile] for control group was 321 [211, 490] compared to 340 [210, 443] and 327 [250, 545], p = 0.998 and p = 0.540, for HH and HC treatment groups, respectively). The percentage of patients receiving transfusion was not different among the groups. CONCLUSION: Higher heparin dosing accomplished by either activated clot time or HC monitoring did not reduce 24-hour intensive care unit blood loss or transfusion requirements.

Analysis of the ESC/EACTS 2020 Atrial Fibrillation Guidelines With Perioperative Implications.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide, with an individual lifetime risk of approximately 37% in the United States. Broadly defined as a supraventricular tachyarrhythmia with disorganized atrial activation, AF results in an increased risk of stroke, heart failure, valvular heart disease, and impaired quality of life, and confers a significant burden on the health of individuals and society. AF in the perioperative setting is common and a significant source of perioperative morbidity and mortality worldwide. The latest iteration of the European Society of Cardiology AF guidelines published in 2020 provide the clinician a valuable road map for the management of this arrythmia. This expert review will comprehensively analyze the 2020 European Society of Cardiology guidelines and provide perioperative management tools for the clinician.

The Success of a Simulation-Based Transesophageal Echocardiography Course for Liver Transplant Anesthesiologists.

INTRODUCTION: Transesophageal echocardiography (TEE) is increasingly used for intraoperative management during orthotopic liver transplantation. Proficient TEE use requires skill and knowledge to accurately assess the hemodynamic status and guide clinical management. Currently there are no TEE educational tracks specifically focused on perioperative liver transplant management and barriers to obtaining basic certification exist. METHODS: A 4-hour simulation-based learning (SBL) course was provided to improve liver transplant anesthesiologist TEE knowledge and skill. Learners received training and education using a TEE simulator in small groups focusing on basic image acquisition, relevant anatomy, hemodynamic calculations, and pathology germane to the liver transplant period. Knowledge assessment and survey responses were assessed at the beginning and completion of the course. Learners completed TEE examinations with simulated pathology during high-fidelity simulations following the course. RESULTS: Seventeen anesthesiologists completed the course. The median baseline knowledge assessment score was 55.0% (37-70). The median postcourse knowledge assessment score improved to 95.0% (94-100) (P < .001). All anesthesiologists were able to identify TEE pathology during high-fidelity simulation. Survey responses yielded significant median score improvement in all areas assessed using a 5-point Likert scale. CONCLUSIONS: A small group, simulation TEE course delivered over 4 hours can increase knowledge and skill in TEE use for liver transplant anesthesiologists.

Evaluation of a Video-Assisted Patient Education Program to Reduce Blood Pressure Delivered Through the Electronic Medical Record: Results of a Quality Improvement Project.

BACKGROUND: Low-cost, automated interventions that increase knowledge and skills around diet and lifestyle modifications are recommended for cardiovascular disease risk reduction. METHODS: We initiated a quality improvement program to assess the impact of a web-based diet and lifestyle intervention utilizing short animated videos in adults with high blood pressure (BP) at a primary care clinic in Saudi Arabia. We enrolled adults with elevated BP, not on BP medications, who were identified using the electronic medical record. We delivered a web-linked diet and lifestyle intervention using animated videos covering diet and lifestyle topics. Videos and reminders were sent weekly for 5 weeks. Outcomes were proportion who engaged in the program, returned for a repeat BP within 3 months, and change in BP. RESULTS: We enrolled 269 adult participants, with a mean (SD) age of 41.6 (12.4) years; 77% were male. At the conclusion of the pilot, we demonstrated a high level of engagement: overall, 69% of materials were viewed and 67% of patients returned for BP. Patients who returned had a mean (SD) baseline systolic BP of 138.0 (7.2) mm Hg and a large mean reduction in systolic BP from baseline, -10.5 mm Hg (12.4; P < 0.001). CONCLUSIONS: Overall, the feasibility of a video-assisted, web-based, diet and lifestyle intervention as a support tool for hypertension management demonstrated a high participation rate and a high return rate for reassessment of BP. These findings suggest that this low-cost, automated intervention may have a great potential as a scalable tool for blood pressure management. However, randomized trials to understanding the effectiveness of the support tools are needed.

Platelet transfusion: The effects of a fluid warmer on platelet function.

Platelet (PLT) transfusions are an important component of hemostatic resuscitation. The AABB has published several guidelines recommending that PLT units should not be infused through blood warming devices. STUDY DESIGN AND METHODS: Thirty-one units of hospital blood bank apheresis PLTs were obtained. PLT-rich plasma (PRP) aggregometry and thromboelastography (TEG) were performed on the unit samples before and after the units were infused through a Ranger blood/fluid warming device. RESULTS: There were no differences in any of the aggregometry results before and after infusion of the PLTs through the blood warmer (all P > .32). There was a significant reduction in the TEG maximum amplitude (MA) of 69.8 ± 7.9 mm before and 66.0 ± 8.8 mm after (P < .001) infusion of the PLTs through the blood warmer and α angle 61.8 ± 9.4° before and 59.3 ± 8.2° after (P = .044) infusion of the PLTs through the blood warmer, although both mean values were within normal range for the TEG and not clinically significant. There were very good correlations of aggregometry and TEG results before and after infusion of the PLTs through the blood warmer device. CONCLUSION: This study did not demonstrate significant deleterious effect on PLT function from infusing apheresis PLT units through a blood warming device by PRP aggregometry. We did detect a statistically significant-but not clinically significant-reduction in TEG MA and α angle. The prohibition of transfusing PLT units though the Ranger blood warming device is not indicated.

Anesthetic considerations for combined heart--liver transplantation in patients with Fontan-associated liver disease.

PURPOSE OF REVIEW: The success of the Fontan procedure has led to increased survival of patients born with certain congenital heart disease to the point that new sequlae, as a result of Fontan circulation, are being discovered. Included among these is Fontan-associated liver disease (FALD). The purpose of this review is to present available literature on the perioperative management of the combined heart--liver transplantation (CHLT) in patients with FALD. RECENT FINDINGS: The perioperative management of a combined heart-liver transplant in a patient with Fontan circulation is complex. The patient is at risk for hemodynamic disturbances, significant blood loss, coagulopathies, and metabolic derangements. The maintenance of an appropriate transpulmonary pressure gradient is paramount to success. Postoperative management should be accomplished by a multidisciplinary care team. Limited series have demonstrated good outcomes in patients who have undergone CHLT. SUMMARY: The perioperative management of CHLT in patients with FALD is complex and available literature is limited. Future studies are needed to further assess proper perioperative management of patients with FALD who undergo CHLT.

Comparison of [11C]-PBR28 Binding Between Persons Living With HIV and HIV-Uninfected Individuals.

OBJECTIVE: Despite combined antiretroviral therapy, neuroinflammation may persist in persons living with HIV (PLWH) and contribute to cognitive impairment in this population. Positron emission tomography (PET) imaging targeting 18 kDa translocator protein (TSPO) has been used to localize neuroinflammation. We aimed to use TSPO-PET imaging to evaluate neuroinflammation in PLWH. DESIGN: Twenty-four virologically suppressed PLWH on combined antiretroviral therapy and 13 HIV-negative (HIV-) controls completed TSPO-PET imaging using the radiotracer [C]PBR28. Because of tracer complexity and differing procedures used in previous studies, we employed an expansive methodological approach, using binding potential (BP) and standard uptake value ratio and multiple different reference regions to estimate [C]PBR28 binding. METHODS: [C]PBR28 binding was measured in 30 cortical and subcortical regions and compared between PLWH and HIV- controls. Pearson correlation evaluated the association between [C]PBR28 binding and cognition and clinical measures of HIV. RESULTS: Analyses conducted using multiple reference regions and measures of tracer uptake revealed no significant differences between [C]PBR28 binding in PLWH compared with HIV- controls. In addition, [C]PBR28 binding in PLWH was not significantly associated with clinical measures of HIV or plasma biomarkers of inflammation. [C]PBR28 binding was not significantly elevated in cognitively impaired PLWH compared with unimpaired PLWH, but there were inverse relationships between cognitive performance (executive and global function) and [C]PBR28 binding in PLWH. CONCLUSIONS: Our results suggest that neuroinflammation may play a role in cognitive deficits, but overall neuroinflammatory levels as measured by TSPO-PET imaging in PLWH are not significantly different from those seen in HIV- controls.

Tau PET in autosomal dominant Alzheimer's disease: relationship with cognition, dementia and other biomarkers.

Tauopathy is a hallmark pathology of Alzheimer's disease with a strong relationship with cognitive impairment. As such, understanding tau may be a key to clinical interventions. In vivo tauopathy has been measured using cerebrospinal fluid assays, but these do not provide information about where pathology is in the brain. The introduction of PET ligands that bind to paired helical filaments provides the ability to measure the amount and distribution of tau pathology. The heritability of the age of dementia onset tied to the specific mutations found in autosomal dominant Alzheimer's disease families provides an elegant model to study the spread of tau across the course of the disease as well as the cross-modal relationship between tau and other biomarkers. To better understand the pathobiology of Alzheimer's disease we measured levels of tau PET binding in individuals with dominantly inherited Alzheimer's disease using data from the Dominantly Inherited Alzheimer Network (DIAN). We examined cross-sectional measures of amyloid-ß, tau, glucose metabolism, and grey matter degeneration in 15 cognitively normal mutation non-carriers, 20 asymptomatic carriers, and 15 symptomatic mutation carriers. Linear models examined the association of pathology with group, estimated years to symptom onset, as well as cross-modal relationships. For comparison, tau PET was acquired on 17 older adults with sporadic, late onset Alzheimer disease. Tau PET binding was starkly elevated in symptomatic DIAN individuals throughout the cortex. The brain areas demonstrating elevated tau PET binding overlapped with those seen in sporadic Alzheimer's disease, but with a greater cortical involvement and greater levels of binding despite similar cognitive impairment. Tau PET binding was elevated in the temporal lobe, but the most prominent loci of pathology were in the precuneus and lateral parietal regions. Symptomatic mutation carriers also demonstrated elevated tau PET binding in the basal ganglia, consistent with prior work with amyloid-ß. The degree of tau tracer binding in symptomatic individuals was correlated to other biomarkers, particularly markers of neurodegeneration. In addition to the differences seen with tau, amyloid-ß was increased in both asymptomatic and symptomatic groups relative to non-carriers. Glucose metabolism showed decline primarily in the symptomatic group. MRI indicated structural degeneration in both asymptomatic and symptomatic cohorts. We demonstrate that tau PET binding is elevated in symptomatic individuals with dominantly inherited Alzheimer's disease. Tau PET uptake was tied to the onset of cognitive dysfunction, and there was a higher amount, and different regional pattern of binding compared to late onset, non-familial Alzheimer's disease.

Assessing the flow to low-income urban areas of conservation and environmental funds approved by California's Proposition 84.

Government funding accounts for a large proportion of conservation and environmental improvements, and is often the result of citizen votes on state ballot measures. A key concern surrounding public investments in the environment is whether that funding serves lower-income communities, which are often the communities of greatest need. We applied three statistical methods to analyze the spatial distribution of conservation funding derived from California's Proposition 84, which distributed nearly $4 billion across California between 2006 and 2015. First, we used hurdle models to ask if income, population density, urban coverage, or pollution could explain receipt of grants or magnitude of funding. Second, we compared the income levels of funded and unfunded communities for each chapter of the proposition. Finally, we examine two sections of the proposition that were intended to fund parks around the state and compare the attributes of funded and unfunded communities. Proposition 84 offers lessons for environmental legislation and future research. While there were general tendencies for more funding to flow to poor areas and areas with pollution problems, the language in Proposition 84 as a whole was vague with respect to the funding of disadvantaged areas, and as a result the targeting of these areas overall was at best modest. However, when enabling legislation (AB 31) defined specific "metrics of disadvantage" that had to be met by communities to receive funds from some sections of Proposition 84, the funds did flow much more selectively to poorer communities. This suggests that future ballot measures should be very explicit in their language if they want to promote equity in conservation investments, and that future research should investigate the extent to which technical workshops and outreach could further increase the number of funded grant proposals from low-income communities.

Generation of 3D Soluble Signal Gradients in Cell-Laden Hydrogels Using Passive Diffusion.

Soluble signal gradients play an important role in organ patterning, cell migration, and differentiation. Currently, signal gradients in 2D cell culture are realized using microfluidics and here cells are exposed to high and nonphysiological shear stress. Tissue morphogenesis (organogenesis) however occurs in 3D and therefore there is a need for simple and practical systems to impose gradients to cells dispersed in 3D matrix. Herein, a 3D gradient generator based on passive diffusion elements that recapitulates interstitial flow and is capable of imposing predictable gradients over long length scales (6 mm) lasting up to 48 h to cells dispersed in a hydrogel environment is reported. Using recombinant human WNT3A (rhWNT3A), the spatiotemporal activation of the canonical WNT pathway in human epithelial kidney cells and human mesenchymal stems cells expressing a green fluorescence protein reporter on a transcription factor/lymphoid enhancer-binding factor (TCF/LEF) promoter is demonstrated. By refining computation models based on experimental findings, the diffusion coefficient of rhWNT3A in presence of human cells in 3D is determined. Furthermore, the formation of rhBMP4 gradients is visualized using immunohistochemistry by staining for phospho-SMAD1/5, the downstream targets of the bone morphogenetic protein (BMP) pathway. The simplicity of the gradient generator is expected to spur its adoption in studying developmental biology paradigms in vitro.

How the International Special Training Centre Is Training World-Class Medics: An Outline of the NATO Special Operations Combat Medic Course.

The North Atlantic Treaty Organization (NATO) Special Operations Combat Medic (NSOCM) course is specifically designed to train 24 highly selected Special Operations Forces (SOF) members to treat trauma and nontrauma patients who have life-threatening diseases and/or injuries. The NSOCM course is held at the International Special Training Centre (ISTC) in Pfullendorf, Germany, and exemplifies ISTC's mission to build interoperability and strengthening alliances between multinational partners. The 24-week NSOCM course is taught by subject matter experts and SOF members from around the globe. Building interoperability and capacity with common NATO standards is crucial to medical support of all future SOF missions where military units and other small elements will be vitally dependent on each other for combined missions at the regional, national, or NATO level. A better understanding and knowledge of the current SOF medic role and the capabilities they need to bring to the battlefield will help advance their scope from the "classic" trauma scenarios to the more advanced clinical medicine and prolonged field care situations. The NSOCM must become a critical-thinker and be able to recognize and treat these health risks and conditions in remote, austere environments, finding the right solution with a limited arsenal at their disposal. The ISTC-NSOCM course is designed to help bridge this gap and raise situational awareness for the NATO on-the-ground medical professionals to ensure "the more they know the more apt they are to save a life." In essence, it is ISTC's goal to meet these challenges by training NSOCMs to meet these multidimensional demands. This article outlines ISTC's development and design of the NSOCM course and new adaptations as we move forward into our third year of training world-class medics.

Loss of white matter integrity reflects tau accumulation in Alzheimer disease defined regions.

OBJECTIVE: White matter (WM) projections were assessed from Alzheimer disease (AD) gray matter regions associated with ß-amyloid (Aß), tau, or neurodegeneration to ascertain relationship between WM structural integrity with Aß and/or tau deposition. METHODS: Participants underwent diffusion tensor imaging (DTI), PET Aß ([18F]AV-45 [florbetapir]), and PET tau ([18F]AV-1451 [flortaucipir]) imaging. Probabilistic WM summary and individual tracts were created from either a composite or individual gray matter seed regions derived from Aß, tau, and neurodegeneration. Linear regressions were performed for Aß, age, tau and WM hyperintensities (WMH) to predict mean diffusivity (MD) or fractional anisotropy (FA) from the corresponding WM summaries or tracts. RESULTS: Our cohort was composed of 59 cognitively normal participants and 10 cognitively impaired individuals. Aß was not associated with DTI metrics in WM summary or individual tracts. Age and WMH strongly predicted MD and FA in several WM regions, with tau a significant predictor of MD only in the anterior temporal WM. CONCLUSION: Tau, not Aß, was associated with changes in anterior temporal WM integrity. WMH, a proxy for vascular damage, was strongly associated with axonal damage, but tau independently contributed to the model, suggesting an additional degenerative mechanism within tracts projecting from regions vulnerable to AD pathology. WM decline was associated with early tau accumulation, and further decline may reflect tau propagation in more advanced stages of AD.

Aerobic glycolysis and tau deposition in preclinical Alzheimer's disease.

Research of the human brain metabolism in vivo has largely focused on total glucose use (via fluorodeoxyglucose positron emission tomography) and, until recently, did not examine the use of glucose outside oxidative phosphorylation, which is known as aerobic glycolysis (AG). AG supports important functions including biosynthesis and neuroprotection but decreases dramatically with aging. This multitracer positron emission tomography study evaluated the relationship between AG, total glucose use (CMRGlc), oxygen metabolism (CMRO2), tau, and amyloid deposition in 42 individuals, including those at preclinical and symptomatic stages of Alzheimer's disease. Our findings demonstrate that in individuals with amyloid burden, lower AG is associated with higher tau deposition. No such correlation was observed for CMRGlc or CMRO2. We suggest that aging-related loss of AG leading to decreased synaptic plasticity and neuroprotection may accelerate tauopathy in individuals with amyloid burden. Longitudinal AG and Alzheimer's disease pathology studies are needed to verify causality.

Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study.

BACKGROUND: Models of Alzheimer's disease propose a sequence of amyloid ß (Aß) accumulation, hypometabolism, and structural decline that precedes the onset of clinical dementia. These pathological features evolve both temporally and spatially in the brain. In this study, we aimed to characterise where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal. METHODS: Between Jan 1, 2009, and Dec 31, 2015, we analysed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers from families carrying gene mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) enrolled in the Dominantly Inherited Alzheimer's Network. We analysed 11C-Pittsburgh Compound B (11C-PiB) PET, 18F-Fluorodeoxyglucose (18F-FDG) PET, and structural MRI data using regions of interest to assess change throughout the brain. We estimated rates of biomarker change as a function of estimated years to symptom onset at baseline using linear mixed-effects models and determined the earliest point at which biomarker trajectories differed between mutation carriers and non-carriers. This study is registered at ClinicalTrials.gov (number NCT00869817) FINDINGS: 11C-PiB PET was available for 346 individuals (162 with longitudinal imaging), 18F-FDG PET was available for 352 individuals (175 with longitudinal imaging), and MRI data were available for 377 individuals (201 with longitudinal imaging). We found a sequence to pathological changes, with rates of Aß deposition in mutation carriers being significantly different from those in non-carriers first (across regions that showed a significant difference, at a mean of 18·9 years [SD 3·3] before expected onset), followed by hypometabolism (14·1 years [5·1] before expected onset), and lastly structural decline (4·7 years [4·2] before expected onset). This biomarker ordering was preserved in most, but not all, regions. The temporal emergence within a biomarker varied across the brain, with the precuneus being the first cortical region for each method to show divergence between groups (22·2 years before expected onset for Aß accumulation, 18·8 years before expected onset for hypometabolism, and 13·0 years before expected onset for cortical thinning). INTERPRETATION: Mutation carriers had elevations in Aß deposition, reduced glucose metabolism, and cortical thinning compared with non-carriers which preceded the expected onset of dementia. Accrual of these pathologies varied throughout the brain, suggesting differential regional and temporal vulnerabilities to Aß, metabolic decline, and structural atrophy, which should be taken into account when using biomarkers in a clinical setting as well as designing and evaluating clinical trials. FUNDING: US National Institutes of Health, the German Center for Neurodegenerative Diseases, and the Medical Research Council Dementias Platform UK.