Integrated multimodal cell atlas of Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research at SEA-AD.org.

Protocol for the Systematic Fixation, Circuit-Based Sampling, and Qualitative and Quantitative Neuropathological Analysis of Human Brain Tissue.

Human brain tissue has long been a critical resource for neuroanatomy and neuropathology, but with the advent of advanced imaging and molecular sequencing techniques, it has become possible to use human brain tissue to study, in great detail, the structural, molecular, and even functional underpinnings of human brain disease. In the century following the first description of Alzheimer's disease (AD), numerous technological advances applied to human tissue have enabled novel diagnostic approaches using diverse physical and molecular biomarkers, and many drug therapies have been tested in clinical trials (Schachter and Davis, Dialogues Clin Neurosci 2:91-100, 2000). The methods for brain procurement and tissue stabilization have remained somewhat consistently focused on formalin fixation and freezing. Although these methods have enabled research protocols of multiple modalities, new, more advanced technologies demand improved methodologies for the procurement, characterization, stabilization, and preparation of both normal and diseased human brain tissues. Here, we describe our current protocols for the procurement and characterization of fixed brain tissue, to enable systematic and precisely targeted diagnoses, and describe the novel, quantitative molecular, and neuroanatomical studies that broadly expand the use of formalin-fixed, paraffin-embedded (FFPE) tissue that will further our understanding of the mechanisms underlying human neuropathologies.

Transcutaneous carbon dioxide monitoring to avoid hypercapnia during complex catheter ablations: a feasibility study.

PURPOSE: The aim of this study was to determine if transcutaneous CO(2) monitoring (TCO(2)) is feasible to avoid hypercapnia during complex catheter ablation. Cumulative analgesic and anxiolytic effects during complex catheter ablation can rarely provoke hypoventilation and respiratory complications. End tidal CO(2) monitors have limitations in non-ventilated patients, and frequent arterial blood gas sampling is impractical. METHODS: Consecutive patients undergoing catheter ablation for atrial fibrillation (AF) or ventricular tachycardia (VT) received continuous TCO(2) monitoring. Procedural evaluation of TCO(2) was performed concomitantly with point-of-care arterial blood gas testing. Endpoints included PCO(2) protocol feasibility, TCO(2)/PCO(2) agreement, and avoidance of hypercapnia-related procedural complications. RESULTS: Fifty patients [AF n = 36 (72 %), VT n = 14 (28 %)] underwent catheter ablation (mean 221.7 ± 57.0 min duration, median 41.4 ± 21.1 min fluoroscopy) in which 6.0 ± 2.6 mg midazolam and 449 ± 225.5 mcg of fentanyl were administered. Monitoring protocol implementation was feasible in 50/50 (100 %) cases. Protocol-driven anesthesia consultation avoided an unplanned intubation in 1 case (2 %) and there was only 1 unplanned intubation (2 %) for oxygen desaturation due to heart failure without hypercapnia during a VT ablation (TCO(2)/PCO(2) agreement <5 mmHg). There were no respiratory or pulseless electrical arrests (0 %) in the study. TCO(2) and PCO(2) correlated well (baseline: r = 0.75, p < 0.001; 1 h:r= 0.72, p < 0.001; 2 h: r = 0.55, p = 0.003; 3 h: r = 0.79, p = 0.02). However, desired agreement was lower than expected [baseline: 33/50 (66 %) < 5 mmHg, 48/50 (96 %) <10 mmHg; 1 h: 29/45 (64 %) < 5 mmHg, 39/45 (87 %) < 10 mmHg; 2 h: 14/26 (54 %) < 5 mmHg, 22/26 (85 %) < 10 mmHg; 3 h: 7/11 (64 %) < 5 mmHg, 10/11 (91 %) < 10 mmHg; >3 h: 1/3 (33 %) < 5 mmHg, 2/3 (66 %) < 10 mmHg]. CONCLUSION: Transcutaneous CO2 monitoring is feasible during complex catheter ablation and correlates with invasively obtained data. However, further development is needed to achieve the desired level of agreement.

Suppressed accumulation of cerebral amyloid {beta} peptides in aged transgenic Alzheimer's disease mice by transplantation with wild-type or prostaglandin E2 receptor subtype 2-null bone marrow.

A complex therapeutic challenge for Alzheimer's disease (AD) is minimizing deleterious aspects of microglial activation while maximizing beneficial actions, including phagocytosis/clearance of amyloid beta (Abeta) peptides. One potential target is selective suppression of microglial prostaglandin E(2) receptor subtype 2 (EP2) function, which influences microglial phagocytosis and elaboration of neurotoxic cytokines. To test this hypothesis, we transplanted bone marrow cells derived from wild-type mice or mice homozygous deficient for EP2 (EP2(-/-)) into lethally irradiated 5-month-old wild-type or APPswe-PS1DeltaE9 double transgenic AD mouse model recipients. We found that cerebral engraftment by bone marrow transplant (BMT)-derived wild-type or EP2(-/-) microglia was more efficient in APPswe-PS1DeltaE9 than in wild-type mice, and APPswe-PS1DeltaE9 mice that received EP2(-/-) BMT had increased cortical microglia compared with APPswe-PS1DeltaE9 mice that received wild-type BMT. We found that myeloablative irradiation followed by bone marrow transplant-derived microglia engraftment, rather than cranial irradiation or BMT alone, was responsible for the approximate one-third reduction in both Abeta plaques and potentially more neurotoxic soluble Abeta species. An additional 25% reduction in cerebral cortical Abeta burden was achieved in mice that received EP2(-/-) BMT compared with mice that received wild-type BMT. Our results provide a foundation for an adult stem cell-based therapy to suppress soluble Abeta peptide and plaque accumulation in the cerebrum of patients with AD.