Jeffrey N. Browndyke

Background: Alterations in intraoperative electroencephalography (EEG) alpha power and anesthetic dose-adjusted EEG alpha power (ADA-FP alpha power) have been associated with both preoperative cognitive impairment and postoperative delirium (POD) among older surgical patients, yet the neurologic underpinnings of alterations in these anesthetic brain response patterns are unknown. Methods: We conducted a single center prospective observational cohort study (ALADDIN), of older adults undergoing non-cardiac/non-cranial surgery, which included preoperative structural and resting state functional MRI, lumbar punctures to obtain CSF, 32 channel intraoperative EEG recordings, and repeated POD assessments. To account for anesthetic dose, frontoparietal EEG alpha power (ADA-FP alpha power) was adjusted using our established formula: [intraoperative alpha power]/(2.5 - end-tidal MAC fraction). Multivoxel pattern analysis (MVPA) with follow-up seed-to-voxel analyses identified functional connectivity patterns associated with intraoperative ADA-FP alpha power. Voxel-wise regression analysis with threshold free cluster estimation (TFCE) correction was used to evaluate associations between cortical thickness and ADA-FP alpha power. CSF biomarker values were obtained from NULISA proximity extension assays. Delirium incidence and severity was assessed with the 3-Minute Diagnostic Confusion Assessment Method (3D-CAM). Delirium severity area under the curve (AUC) during hospitalization was defined as the sum of all 3D-CAM delirium severity scores within the postoperative hospitalization period (for up to 7 days after surgery). The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) was used in cases of non-verbal/intubated patients. Results: ALADDIN enrolled 215 patients, of whom 168 underwent surgery and had high-quality intraoperative EEG data (44.6% female; mean age 70.9 years). MVPA showed that ADA-FP alpha power was associated with altered functional connectivity within the bilateral frontal poles, left superior frontal gyrus and the right superior parietal lobule (p-FWE < 0.05). Seed-to-voxel analyses revealed that higher ADA-FP alpha power was associated with increased connectivity between DMN MVPA regions and DMN, DAN and salience/ventral attention and decreased connectivity with visual regions. Conversely, right superior parietal lobule connectivity shifted towards greater DMN segregation and increased somatosensory/motor coupling (p-FWE < 0.05). Lower ADA-FP alpha power was also associated with lower cortical thickness in left occipitotemporal and superior parietal cortices (TFCE-corrected p < 0.05). ADA-FP alpha power was also lower among participants with (vs those without) postoperative ward/floor delirium (mean difference, 1.33; 95% CI, 0.22 to 2.44; p=0.019), and ADA-FP alpha power was inversely associated with peak delirium severity (spearman's rho = -0.26; 95% CI, -0.40 to -0.11; p <0.001) and delirium severity AUC (spearman's rho = -0.28; 95% CI, -0.42 to -0.13; p < 0.001). Discussion: These findings suggest a functional and structural neuroanatomic basis for the decreased EEG ADA-FP alpha power values seen among some older surgical patients, which may explain the association between decreased EEG ADA-FP alpha power and increased rates of both preoperative cognitive impairment and postoperative delirium. More specifically, these findings suggest that altered default mode and dorsal attention network connectivity is linked to decreased EEG ADA-FP alpha power and raise the possibility that preoperative/baseline functional connectivity alterations within these networks may play a role in delirium risk.

BACKGROUND: Postoperative increases in cerebrospinal fluid (CSF) to plasma albumin ratio (CPAR), a blood-brain barrier dysfunction marker, have been associated with postoperative delirium (POD) and prolonged hospital stay. However, the contributions of plasma versus CSF albumin changes remain unclear. AIM: To determine whether 24-hour postoperative changes in plasma and CSF albumin are independently associated with POD and hospital length of stay. METHODS: Plasma and CSF albumin concentrations were measured before and 24-hours postoperatively in older non-cardiac surgery patients. Multivariable logistic and negative binomial regression models evaluated associations between albumin changes and POD or hospital length of stay, adjusting for age, baseline cognition, surgery type, and fluid administration. RESULTS: Of 240 patients, 31 (13.3%) developed POD. From before to 24-hours after surgery, both plasma albumin (median 3.95 to 3.43 g/dL, p<0.001) and CSF albumin decreased (median 22.68 to 20.43 mg/dL, p<0.001). Greater plasma albumin decreases (per 0.43 g/dL) were independently associated with POD (OR 2.14, 95% CI 1.28-3.58; p=0.004) and longer hospital stay (mean ratio 1.44, 95% CI 1.26-1.64; p<0.001). In contrast, CSF albumin changes (per 5.8 mg/dL higher) were not associated with POD (OR 0.97, 95% CI 0.60-1.58; p=0.91) but were modestly associated with longer hospital stay (mean ratio 1.17, 95% CI 1.04-1.32; p=0.01). CONCLUSIONS: Plasma and CSF albumin decreased postoperatively, but only plasma decreases were associated with POD. These results suggest that associations between CPAR increases and POD may be due to postoperative plasma albumin decreases and highlight limitations of CPAR as a standalone marker of postoperative BBB dysfunction.

Background: Excessive daytime sleepiness may reflect increased vulnerability to postoperative neurocognitive disorders given its association with neurodegenerative disease, cognitive decline, and dementia. However, the role of excessive daytime sleepiness in postoperative neurocognitive disorders is unknown. Here, we investigated whether preoperative moderate–severe excessive daytime sleepiness is associated with postoperative neurocognitive disorder severity. Methods: This prospective observational cohort study included older non‐cardiac surgery patients who completed preoperative Epworth sleepiness scale questionnaires, home sleep apnea testing, and pre‐ and postoperative delirium assessments and cognitive testing. Cognitive scores were combined with reflective factor analysis into a global cognitive index. Moderate–severe excessive daytime sleepiness was defined as an Epworth Sleepiness Scale score greater than 12. Postoperative neurocognitive disorder severity was assessed by the global cognitive index change from before to 6‐weeks and 1‐year after surgery. Results: Of the 96 subjects who completed testing, 11 subjects exhibited moderate–severe excessive sleepiness. In a multivariable analysis adjusting for prespecified confounders and precision variables (age, sex, respiratory event index, baseline cognitive performance and surgery duration), moderate–severe EDS was significantly associated with 6‐week postoperative change in global cognition (mean difference −0.24; 95% CI −0.48, −0.004; p = 0.046), but was not associated with peak postoperative delirium severity scores (OR 3.66; 95% CI, 0.96, 13.91; p = 0.057). Conclusions: Preoperative moderate–severe EDS is associated with decreased 6‐week postoperative global cognitive performance after adjustment for relevant confounders and precision variables. These results suggest that pre‐existing moderate–severe excessive daytime sleepiness is a risk factor for increased postoperative neurocognitive disorder severity. Trial Registration: clinicaltrials.gov : NCT03273335.

Neuroinflammation has detrimental neurocognitive effects in patients with systemic and neuropsychiatric diseases. Yet, outside of these conditions, it is u

BACKGROUND: Postoperative delirium is the most common postsurgical complication in older adults and is associated with an increased risk of long-term cognitive decline and Alzheimer’s disease (AD) and related dementias (ADRD). However, the neurological basis of this increased risk—whether postoperative delirium unmasks latent preoperative pathology or leads to AD-relevant pathology after perioperative brain injury—remains unclear. METHODS: To investigate potential brain microstructural abnormalities associated with postoperative delirium and cognitive function, we analyzed pre- and post-operative Neurite Orientation Dispersion and Density Imaging (NODDI) MRI data within the posterior cingulate cortex (PCC) from 110 patients aged ≥60 years who underwent non-cardiac/non-intracranial surgery. RESULTS: We found increased free water (FISO) and decreased neurite density index (NDI) and orientation dispersion index (ODI) in the dorsal PCC before surgery among those who later developed postoperative delirium (n = 12) versus those who did not (n = 98). Preoperative dorsal PCC NDI and ODI values were also positively associated with preoperative attention/concentration performance, independent of age, education level, and global brain atrophy (NDI: = 0.29 (95% CI, 0.10–0.50), P = .008; ODI: = 0.29 (95% CI, 0.03–0.44), P = .004). Yet, these diffusion metrics were not correlated with cerebrospinal fluid amyloid beta (Aβ) positivity or levels. CONCLUSIONS: These results suggest that preoperative latent brain abnormalities within the dorsal PCC may underlie attention/concentration deficits and susceptibility to postoperative delirium, yet these dorsal PCC NODDI abnormalities were not significantly associated with CSF Aβ levels (a measure of brain Amyloid deposition). Our findings highlight microstructural vulnerability within the PCC, a key region of the default mode network, as a neuroanatomic locus that can help explain the link between preoperative attention/concentration deficits and increased postoperative delirium risk among vulnerable older surgical patients.

Innovation in the treatment of ascending aorta and arch pathology with novel catheter-based and hybrid procedures has driven the need for a strategy to guide their safe application. The ARCH-ARC (Aortic Arch Academic Research Consortium) was established to pragmatically develop consistent clinical end points and to standardize definitions for use in studies of these new technologies. The ARCH-ARC team, consisting of independent international specialists in cardiac surgery, vascular surgery, vascular medicine, cardiology, neurology, radiology, and clinical trials, along with US Food and Drug Administration, industry, and contract research organization representatives, held virtual meetings from 2021 to 2025. Consensus was used to identify appropriate clinical end points and to standardize definitions of end points for endovascular, hybrid, and open surgical procedures in clinical trials in the ascending aorta and arch. Drawing on previous ARC work in cardiac, neurological, renal, and bleeding end points, the ARCH-ARC focused on definitions and end points related to aortic arch–specific anatomy, pathology, and procedures and clinical, device, and imaging. The adoption of the ARCH-ARC consensus definitions and end points will provide a template for consistent adjudication and event reporting and facilitate comparisons of clinical research studies involving devices for ascending aorta and arch pathology.

Alzheimer’s disease currently has no cure and is usually detected too late for interventions to be effective. In this study we have focused on cognitively normal subjects to study the impact of risk factors on their long-range brain connections. To detect vulnerable connections, we devised a multiscale, hierarchical method for spatial clustering of the whole brain tractogram and examined the impact of age and APOE allelic variation on cognitive abilities and bundle properties including texture e.g., mean fractional anisotropy, variability, and geometric properties including streamline length, volume, shape, as well as asymmetry. We found that the third level subdivision in the bundle hierarchy provided the most sensitive ability to detect age and genotype differences associated with risk factors. Our results indicate that frontal bundles were a major age predictor, while the occipital cortex and cerebellar connections were important risk predictors that were heavily genotype dependent, and showed accelerated decline in fractional anisotropy, shape similarity, and increased asymmetry. Cognitive metrics related to olfactory memory were mapped to bundles, providing possible early markers of neurodegeneration. In addition, physiological metrics associated with cardiovascular disease risk were associated with changes in white matter tracts. Our novel method for a data driven analysis of sensitive changes in tractography may differentiate populations at risk for AD and isolate specific vulnerable networks.

Postoperative delirium is the most common postsurgical complication in older adults and is associated with an increased risk of long-term cognitive decline and Alzheimer’s disease (AD) and related dementias (ADRD). However, the neurological basis of this increased risk— whether postoperative delirium unmasks latent preoperative pathology or leads to AD-relevant pathology after perioperative brain injury—remains unclear. Recent advancements in neuroimaging techniques now enable the detection of subtle brain features or damage that may underlie clinical symptoms. Among these, Neurite Orientation Dispersion and Density Imaging (NODDI) can help identify microstructural brain damage, even in the absence of visible macro-anatomical abnormalities. To investigate potential brain microstructural abnormalities associated with postoperative delirium and cognitive function, we analyzed pre- and post-operative diffusion MRI data from 111 patients aged ≥60 years who underwent non-cardiac/non-intracranial surgery. Specifically, we investigated preoperative variation in diffusion metrics within the posterior cingulate cortex (PCC), a region in which prior work has identified glucose metabolism alterations in the delirious brain, and a key region in the early accumulation of amyloid beta (Aβ) in preclinical AD. We also examined the relationship of preoperative PCC NODDI abnormalities with preoperative cognitive function. Compared to patients who did not develop postoperative delirium (n=99), we found increased free water (FISO) and neurite density index (NDI) and decreased orientation dispersion index (ODI) in the dorsal PCC before surgery among those who later developed postoperative delirium (n=12). These FISO differences before surgery remained present at six weeks postoperatively, while these NDI and ODI differences did not. Preoperative dorsal PCC NDI and ODI values were also positively associated with preoperative attention/concentration performance, independent of age, education level, and global brain atrophy. Yet, these diffusion metrics were not correlated with cerebrospinal fluid Aβ positivity or levels. These results suggest that preoperative latent brain abnormalities within the dorsal PCC may underlie susceptibility to postoperative delirium, independent of AD-related (i.e., Aβ) neuropathology. Furthermore, these preoperative microstructural differences in the dorsal PCC were linked to preoperative deficits in attention/concentration, a core feature of postoperative delirium. Our findings highlight microstructural vulnerability within the PCC, a key region of the default mode network, as a neuroanatomic locus that can help explain the link between preoperative attention/concentration deficits and increased postoperative delirium risk among vulnerable older surgical patients.

Alzheimer’s disease currently has no cure and is usually detected too late for interventions to be effective. In this study we have focused on cognitively normal subjects to study the impact of risk factors on their long-range brain connections. To detect vulnerable connections, we devised a multiscale, hierarchical method for spatial clustering of the whole brain tractogram and examined the impact of age and APOE allelic variation on cognitive abilities and bundle properties including texture e.g., mean fractional anisotropy, variability, and geometric properties including streamline length, volume, and shape, as well as asymmetry. We found that the third level subdivision in the bundle hierarchy provided the most sensitive ability to detect age and genotype differences associated with risk factors. Our results indicate that frontal bundles were a major age predictor, while the occipital cortex and cerebellar connections were important risk predictors that were heavily genotype dependent, and showed accelerated decline in fractional anisotropy, shape similarity, and increased asymmetry. Cognitive metrics related to olfactory memory were mapped to bundles, providing possible early markers of neurodegeneration. In addition, physiological metrics such as diastolic blood pressure were associated with changes in white matter tracts. Our novel method for a data driven analysis of sensitive changes in tractography may differentiate populations at risk for AD and isolate specific vulnerable networks.