Risk Of Long-term Cognitive Impairment Research Articles

A transient brain endothelial translatome response to endotoxin is associated with mild cognitive changes post-shock in young mice

Sepsis-associated encephalopathy (SAE) is associated with increased risk of long-term cognitive impairment. SAE is driven, at least in part, by brain endothelial dysfunction in response to systemic cytokine signaling. However, the mechanisms driving SAE and its consequences remain largely unknown. Here, we performed translating ribosome affinity purification and RNA-sequencing (TRAP-seq) from the brain endothelium to determine the transcriptional changes after an acute endotoxemic (LPS) challenge. LPS induced a strong acute transcriptional response in the brain endothelium that partially correlates with the whole brain transcriptional response and suggested an endothelial-specific hypoxia response. Consistent with a crucial role for IL-6, loss of the main regulator of this pathway, SOCS3, leads to a broadening of the population of genes responsive to LPS, suggesting that an overactivation of the IL-6/JAK/STAT3 pathway leads to an increased transcriptional response that could explain our prior findings of severe brain injury in these mice. To identify any potential sequelae of this acute response, we performed brain TRAP-seq following a battery of behavioral tests in mice after apparent recovery. We found that the transcriptional response returns to baseline within days post-challenge, but reductions in gene expression regulating protein translation and respiratory electron transport remained. We observed that mice that recovered from the endotoxemic shock showed mild, sex-dependent cognitive impairment, suggesting that the acute brain injury led to sustained effects. A better understanding of the transcriptional and non-transcriptional changes in response to shock is needed in order to prevent and/or revert the devastating consequences of septic shock.

Acute Kidney Injury, Systemic Inflammation, and Long-Term Cognitive Function: ASSESS-AKI.

Cognitive dysfunction is a well-known complication of chronic kidney disease, but it is less known whether cognitive decline occurs in survivors after acute kidney injury (AKI). We hypothesized that an episode of AKI is associated with poorer cognitive function, mediated, at least in part, by persistent systemic inflammation. ASSESS-AKI enrolled patients surviving three months after hospitalization with and without AKI matched based on demographics, comorbidities, and baseline kidney function. A subset underwent cognitive testing using the modified mini-mental status examination (3MS) at 3, 12, and 36 months. We examined the association of AKI with 3MS scores using mixed linear models and assessed the proportion of risk mediated by systemic inflammatory biomarkers. Among 1538 participants in ASSESS-AKI, 1420 (92%) completed the 3MS assessment at 3 months and had a corresponding matched participant. Participants with AKI had lower 3MS scores at three years (difference -1.1 (95% CI: -2.0, -0.3) P=0.009) compared to participants without AKI. A higher proportion of AKI participants had a clinically meaningful (≥ 5 point) reduction in 3MS scores at three years compared to participants without AKI (14% vs. 10%, P=0.04). In mediation analyses, plasma soluble tumor necrosis factor receptor-1 (sTNFR-1) at three months after AKI mediated 35% (P=0.02) of the AKI related risk for 3MS scores at three years. AKI was associated with lower 3MS scores and sTNFR-1 concentrations appeared to mediate a significant proportion of the risk of long-term cognitive impairment. Further work is needed to determine if AKI is causal or a marker for cognitive impairment.

Functional brain network and trail making test changes following major surgery and postoperative delirium: a prospective, multicentre, observational cohort study

BackgroundDelirium is a frequent complication after surgery in older adults and is associated with an increased risk of long-term cognitive impairment and dementia. Disturbances in functional brain networks were previously reported during delirium. We hypothesised that alterations in functional brain networks persist after remission of postoperative delirium and that functional brain network alterations are associated with long-term cognitive impairment. MethodsIn this prospective, multicentre, observational cohort study, we included older patients who underwent clinical assessments (including the Trail Making Test B [TMT-B]) and resting-state functional MRI (rs-fMRI) before and 3 months after elective surgery. Delirium was assessed on the first seven postoperative days. ResultsOf the 554 enrolled patients, 246 remained after strict motion correction, of whom 38 (16%) developed postoperative delirium. The rs-fMRI functional connectivity strength increased 3 months after surgery in the total study population (β=0.006; 95% confidence interval [CI]: 0.001–0.011; P=0.013), but it decreased after postoperative delirium (β=–0.015; 95% CI: –0.028 to 0.002; P=0.023). No difference in TMT-B scores was found at follow-up between patients with and without postoperative delirium. Patients with decreased functional connectivity strength declined in TMT-B scores compared with those who did not (β=11.04; 95% CI: 0.85–21.2; P=0.034). ConclusionsPostoperative delirium was associated with decreased brain functional connectivity strength after 3 months, suggesting that delirium has a long-lasting impact on brain networks. The decreased connectivity strength was associated with significant cognitive deterioration after major surgery. Clinical trial registrationNCT02265263.

Recent advances and perspectives of postoperative neurological disorders in the elderly surgical patients.

Postoperative neurological disorders, including postoperative delirium (POD), postoperative cognitive dysfunction (POCD), postoperative covert ischemic stroke, and hemorrhagic stroke, are challenging clinical problems in the emerging aged surgical population. These disorders can deteriorate functional outcomes and long‐term quality of life after surgery, resulting in a substantial social and financial burden to the family and society. Understanding predisposing and precipitating factors may promote individualized preventive treatment for each disorder, as several risk factors are modifiable. Besides prevention, timely identification and treatment of etiologies and symptoms can contribute to better recovery from postoperative neurological disorders and lower risk of long‐term cognitive impairment, disability, and even death. Herein, we summarize the diagnosis, risk factors, prevention, and treatment of these postoperative complications, with emphasis on recent advances and perspectives.

Long-term Risk of Cognitive Impairment and Dementia Following Bilateral Oophorectomy in Premenopausal Women—Time to Rethink Policies?

Long-term Risk of Cognitive Impairment and Dementia Following Bilateral Oophorectomy in Premenopausal Women—Time to Rethink Policies?

This Month in Anesthesiology

This Month in Anesthesiology

The Role of Perioperative Sleep Disturbance in Postoperative Neurocognitive Disorders.

Postoperative neurocognitive disorder (PND) increases the length of hospital stay, mortality, and risk of long-term cognitive impairment. Perioperative sleep disturbance is prevalent and commonly ignored and may increase the risk of PND. However, the role of perioperative sleep disturbances in PND remains unclear. Nocturnal sleep plays an indispensable role in learning, memory, and maintenance of cerebral microenvironmental homeostasis. Hospitalized sleep disturbances also increase the incidence of postoperative delirium and cognitive dysfunction. This review summarizes the role of perioperative sleep disturbances in PND and elucidates the potential mechanisms underlying sleep-deprivation-mediated PND. Activated neuroinflammation and oxidative stress; impaired function of the blood-brain barrier and glymphatic pathway; decreased hippocampal brain-derived neurotrophic factor, adult neurogenesis, and sirtuin1 expression; and accumulated amyloid-beta proteins are associated with PND in individuals with perioperative sleep disorders. These findings suggest that the improvement of perioperative sleep might reduce the incidence of postoperative delirium and postoperative cognitive dysfunction. Future studies should further investigate the role of perioperative sleep disturbance in PND.

Cognitive and psychosocial outcomes of mechanically ventilated intensive care patients with and without delirium

ObjectiveDelirium is common in intensive care patients and is associated with short- and long-term adverse outcomes. We investigated the long-term risk of cognitive impairment and post-traumatic stress disorder (PTSD) in intensive care patients with and without delirium.MethodsThis is a prospective cohort study in ICUs in two Australian university-affiliated hospitals. Patients were eligible if they were older than 18 years, mechanically ventilated for more than 24 h and did not meet exclusion criteria. Delirium was assessed using the Confusion Assessment Method for Intensive Care Unit. Variables assessing cognitive function and PTSD symptoms were collected at ICU discharge, after 6 and 12 months: Mini-Mental State Examination, Telephone Interview for Cognitive Status, Impact of Events Scale-Revised and Informant Questionnaire for Cognitive Decline (caregiver).Results103 participants were included of which 36% developed delirium in ICU. Patients with delirium were sicker and had longer duration of mechanical ventilation and ICU length of stay. After 12 months, 41/60 (68.3%) evaluable patients were cognitively impaired, with 11.6% representing the presence of symptoms consistent with dementia. When evaluated by the patient’s caregiver, the patient’s cognitive function was found to be severely impaired in a larger proportion of patients (14/60, 23.3%). Delirium was associated with worse cognitive function at ICU discharge, but not with long-term cognitive function. IES-R scores, measuring PTSD symptoms, were significantly higher in patients who had delirium compared to patients without delirium. In regression analysis, delirium was independently associated with cognitive function at ICU discharge and PTSD symptoms at 12 months.ConclusionsIntensive care survivors have significant rates of long-term cognitive decline and PTSD symptoms. Delirium in ICU was independently associated with short-term but not long-term cognitive function, and with long-term PTSD symptoms.Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12616001116415, 15/8/2016 retrospectively registered, https://www.anzctr.org.au

Long-Term Cognitive Impairment Associated With Delirium in Acute Neurological Injury.

To characterize the risk of long-term cognitive impairment associated with delirium in acute neurologic injury patients. We analyzed a 10-year cohort of adult acute neurologic injury patients (stroke and traumatic brain injury) without preexisting mild cognitive impairment or dementia, utilizing administrative databases. Patients were followed for in-hospital delirium and mild cognitive impairment or dementia. We report incidence and adjusted hazard ratios for mild cognitive impairment or dementia associated with delirium. Subgroups analyzed include acute neurologic injury categories, dementia subtypes, repeated delirium exposure, and age strata. We used state emergency department and state inpatient databases for New York, Florida, and California. All visits are included in the databases regardless of payer status. We included adult patients with diagnosis of stroke and traumatic brain injury as acute neurologic injury. Patients with preexisting mild cognitive impairment or dementia were excluded. None. Among 911,380 acute neurologic injury patients, 5.2% were diagnosed with delirium. Mild cognitive impairment or dementia incidence among delirium patients was approximately twice that of nondelirium patients. In adjusted models, risk of mild cognitive impairment or dementia was higher among patients with delirium (adjusted hazard ratio, 1.58). Increased risk was observed across all subgroups including patients less than or equal to 55 years old. Identification, management, and prevention of in-hospital delirium could potentially improve long-term cognitive outcomes in acute neurologic injury patients.

The rationale of flexible ICU visiting hours for delirium prevention

Delirium is a frequent and severe form of acute brain dysfunction that occurs in the critically ill (1). It currently represents a major challenge for critical care professionals as it is associated with increased mortality, longer intensive care unit (ICU) and hospital stay, increased risk of long-term cognitive impairment, and higher costs of care (2,3). Disappointingly, pharmacologic interventions have a limited role in the prevention and treatment of delirium (4). Conversely, many non-pharmacologic interventions such as reorientation activities, cognitive stimulation, early mobilization, sleep hygiene, and flexibilization of family visits have gained increasing attention due to its low cost and potential to prevent or limit delirium among ICU patients (5,6).

Predicting Long-Term Cognitive Outcome Following Breast Cancer with Pre-Treatment Resting State fMRI and Random Forest Machine Learning.

We aimed to determine if resting state functional magnetic resonance imaging (fMRI) acquired at pre-treatment baseline could accurately predict breast cancer-related cognitive impairment at long-term follow-up. We evaluated 31 patients with breast cancer (age 34–65) prior to any treatment, post-chemotherapy and 1 year later. Cognitive testing scores were normalized based on data obtained from 43 healthy female controls and then used to categorize patients as impaired or not based on longitudinal changes. We measured clustering coefficient, a measure of local connectivity, by applying graph theory to baseline resting state fMRI and entered these metrics along with relevant patient-related and medical variables into random forest classification. Incidence of cognitive impairment at 1 year follow-up was 55% and was predicted by classification algorithms with up to 100% accuracy (p < 0.0001). The neuroimaging-based model was significantly more accurate than a model involving patient-related and medical variables (p = 0.005). Hub regions belonging to several distinct functional networks were the most important predictors of cognitive outcome. Characteristics of these hubs indicated potential spread of brain injury from default mode to other networks over time. These findings suggest that resting state fMRI is a promising tool for predicting future cognitive impairment associated with breast cancer. This information could inform treatment decision making by identifying patients at highest risk for long-term cognitive impairment.

Nurse awareness of patients who may have incident delirium.

Delirium is a disturbance of attention and cognition that cannot be explained by pre-existing neurocognitive disorders. It can have serious consequences, including falls, increased mortality, longer hospital stays and an increased risk of long-term cognitive impairment. Delirium may be present on admission to hospital but, where it is not, nurses should identify people at risk.

Remote Lower White Matter Integrity Increases the Risk of Long-Term Cognitive Impairment After Ischemic Stroke in Young Adults.

Poststroke cognitive impairment occurs frequently in young patients with ischemic stroke (18 through 50 years of age). Accumulating data suggest that stroke is associated with lower white matter integrity remote from the stroke impact area, which might explain why some patients have good long-term cognitive outcome and others do not. Given the life expectancy of decades in young patients, we therefore investigated remote white matter in relation to long-term cognitive function. We included all consecutive first-ever ischemic stroke patients, left/right hemisphere, without recurrent stroke or transient ischemic attack during follow-up, aged 18 through 50 years, admitted to our university medical center between 1980 and 2010. One hundred seventeen patients underwent magnetic resonance imaging scanning including a T1-weighted scan, a diffusion tensor imaging scan, and completed a neuropsychological assessment. Patients were compared with a matched stroke-free control group (age, sex, and education matched). Cognitive impairment was defined as >1.5 SD below the mean cognitive index score of controls and no cognitive impairment as ≤1 SD. Tract-Based Spatial Statistics was used to assess the white matter integrity (fractional anisotropy and mean diffusivity). About 11 years after ischemic stroke, lower remote white matter integrity was associated with a worse long-term cognitive performance. A lower remote white matter integrity, even in the contralesional hemisphere, was observed in cognitively impaired patients (n=25) compared with cognitively unimpaired patients (n=71). These findings indicate that although stroke has an acute onset, it might have long lasting effects on remote white matter integrity and thereby increases the risk of long-term cognitive impairment.

Memory complaints and risk of cognitive impairment after nearly 2 decades among older women.

To investigate the association between subjective memory complaints (SMCs) and long-term risk of cognitive impairment in aging because most previous studies have followed individuals for only a few years. Participants were 1,107 cognitively normal, community-dwelling older women (aged 65 years and older at baseline) in a prospective study of aging. SMCs were assessed shortly after baseline and repeatedly over time with the yes/no question, "Do you feel you have more problems with memory than most?" Cognitive status 18 years later (normal or impaired with mild cognitive impairment or dementia) was determined by an expert panel. Using logistic regression, we investigated the association between SMCs over time and risk of cognitive impairment, adjusting for demographics, baseline cognition, and characteristics that differed between those with and without SMCs. At baseline, 8.0% of participants (n = 89) endorsed SMCs. Baseline SMCs were associated with increased risk of cognitive impairment 18 years later (adjusted odds ratio [OR] = 1.7, 95% confidence interval 1.1-2.8). Results were unchanged after excluding participants with depression. The association between SMCs and cognitive impairment was greatest at the last SMC assessment time point (18 years before diagnosis: adjusted OR = 1.7 [1.1-2.9]; 14 years before diagnosis: adjusted OR = 1.6 [0.9-2.7]; 10 years before diagnosis: adjusted OR = 1.9 [1.1-3.1]; 4 years before diagnosis: adjusted OR = 3.0 [1.8-5.0]). SMCs are associated with cognitive impairment nearly 2 decades later among older women. SMCs may be a very early symptom of an insidious neurodegenerative disease process, such as Alzheimer disease.

Cognitive assessment of very low birth weight infants using the Dutch version of the PARCA-R parent questionnaire

ObjectiveVery low birth weight (VLBW) infants are at an increased risk of long-term cognitive impairment. Early identification and timely interventions are important. We aimed to validate the Dutch version of the revised Parent Report of Children's Abilities (PARCA-R) questionnaire. MethodsThe subjects were survivors from the Belgian participating centers to the NIRTURE trial. As part of a study-related follow-up, PARCA-R was sent out at the age of 2years. As part of a normal hospital follow-up, these infants were assessed by the Bayley Scales of Infant Development — second edition (BSID-II) at the age of 9, 18 and 36months. MRI was performed at term in the group of VLBW infants of ZOL Genk as standard care. ResultsPARCA-R was sent out to 193 surviving infants. BSID-II was performed in 36% (n=70) at 9months, in 30% (n=58) at 18months and in 12% (n=23) at 36months. MRI was available for 32 infants. We received 86 responses to the PARCA-R. Parent report composite (PRC) scores were significantly correlated with the Mental Development Index (MDI) (p<0.0001 (9months); p=0.003 (18months); p=0.01 (36months)). PRC scores were significantly lower in those with an abnormal MRI (92 vs.124; p=0.04). ConclusionWe support the use of the PARCA-R as a time and cost efficient alternative for identifying cognitive delay. Practice implicationsWe suggest that the combination of BSID-II, MRI at term and PARCA-R would be the ideal testing method for identifying VLBW infants at risk for cognitive developmental delay by two years of age.

Can we optimize long-term outcomes in acute respiratory distress syndrome by targeting normoxemia?

Since its original description in 1967, acute respiratory distress syndrome (ARDS) has been recognized as a devastating condition associated with significant morbidity and mortality. Advances in critical care medicine and ARDS management have led to a substantial increase in the number of ARDS survivors. Long-term cognitive impairment after critical illness is a significant public health concern. ARDS survivors frequently experience long-term cognitive impairment, as well as physical impairment, psychiatric morbidity, and reduced health-related quality of life. At present, no intensive care unit-based intervention has been proven to reduce the risk of long-term cognitive impairment after ARDS. To address the urgent need to identify strategies to preserve long-term health, investigators have advocated the measurement of short- and long-term outcomes in clinical trials. Maintaining adequate oxygen delivery to preserve organ function is of vital importance in ARDS management. The optimal target range for arterial oxygenation in ARDS remains unknown, due in part to the challenge to maintain adequate tissue oxygenation and to minimize harm, such as oxygen toxicity. An approach targeted to subnormal oxygenation values (partial pressure of arterial oxygen, 55-80 mm Hg) has emerged as a means to accomplish these aims. In this perspective, we critically evaluate this strategy from short- and long-term perspectives, with a focus on the potential long-term cognitive effects of the strategy. We conclude with a proposal to consider resetting the target range for arterial oxygenation higher (85-110 mm Hg) as a potential strategy to improve the long-term outcomes of ARDS survivors.

Long-Term Cognitive Impairment after Critical Illness

BackgroundSurvivors of critical illness often have a prolonged and disabling form of cognitive impairment that remains inadequately characterized.MethodsWe enrolled adults with respiratory failure or shock in the medical or surgical intensive care unit (ICU), evaluated them for in-hospital delirium, and assessed global cognition and executive function 3 and 12 months after discharge with the use of the Repeatable Battery for the Assessment of Neuropsychological Status (population age-adjusted mean [±SD] score, 100±15, with lower values indicating worse global cognition) and the Trail Making Test, Part B (population age-, sex-, and education-adjusted mean score, 50±10, with lower scores indicating worse executive function). Associations of the duration of delirium and the use of sedative or analgesic agents with the outcomes were assessed with the use of linear regression, with adjustment for potential confounders.ResultsOf the 821 patients enrolled, 6% had cognitive impairment at baseline, and delirium developed in 74% during the hospital stay. At 3 months, 40% of the patients had global cognition scores that were 1.5 SD below the population means (similar to scores for patients with moderate traumatic brain injury), and 26% had scores 2 SD below the population means (similar to scores for patients with mild Alzheimer's disease). Deficits occurred in both older and younger patients and persisted, with 34% and 24% of all patients with assessments at 12 months that were similar to scores for patients with moderate traumatic brain injury and scores for patients with mild Alzheimer's disease, respectively. A longer duration of delirium was independently associated with worse global cognition at 3 and 12 months (P=0.001 and P=0.04, respectively) and worse executive function at 3 and 12 months (P=0.004 and P=0.007, respectively). Use of sedative or analgesic medications was not consistently associated with cognitive impairment at 3 and 12 months.ConclusionsPatients in medical and surgical ICUs are at high risk for long-term cognitive impairment. A longer duration of delirium in the hospital was associated with worse global cognition and executive function scores at 3 and 12 months. (Funded by the National Institutes of Health and others; BRAIN-ICU ClinicalTrials.gov number, NCT00392795.)

What’s new on the post-ICU burden for patients and relatives?

Delirium is common in critical care patients and it has been suggested that it is associated with an increased risk of long-term cognitive impairment [2]. Recent delirium guidelines all emphasise the need for screening for and treating delirium while the patient is in critical care and this is now seen as a high priority. Haloperidol prophylaxis has been shown to be effective in reducing the incidence of delirium in elderly non-cardiac surgery patients admitted to ICU [3], but in a randomised controlled trial (RCT) with critically ill patients there was no advantage [4]. In addition, antipsychotics are not without side effects; even the short-term antipsychotic use when treating delirium may cause QTc interval prolongation or result in extrapyramidal effects.

Delirium and long-term cognitive impairment

Delirium is a severe, acute neuropsychiatric syndrome that is highly prevalent in acute hospital populations. Delirium has noticeable effects on length of hospitalization, cost of care, mortality and morbidity. In addition to these well-established adverse consequences, there is increasing evidence linking delirium and a higher risk of long-term cognitive impairment (LTCI), including dementia. A prior review (Jackson, Gordon, Hart, Hopkins, & Ely, 2004), in which nine studies (total N = 1,885, years 1989–2003) were considered, concluded that there was evidence for an association between delirium and LTCI. Here we provide a review of studies published since Jackson's review. We included nine reports, with a total of 2,025 patients. The studies show diverse sample sizes, methodologies, designs and patient populations. However, taken together, the results of these new studies broadly confirm that there is a link between delirium and LTCI. We go on to discuss putative mechanisms and explanations. These include (1) delirium as a marker of chronic progressive pathology, but unrelated to any progression, (2) delirium as a consequence of acute brain damage which is also responsible for a ‘single hit’ or triggering of active processes causing LTCI, (3) delirium itself as a cause of LTCI, and (4) drug treatment of delirium or other conditions as a cause of LTCI. We conclude with suggestions for future research.

Dexamethasone and long‐term outcome in adults with bacterial meningitis

This follow-up study of the European Dexamethasone Study was designed to examine the potential harmful effect of adjunctive dexamethasone treatment on long-term neuropsychological outcome in adults with bacterial meningitis. Neurological, audiological, and neuropsychological examinations were performed in adults who survived pneumococcal or meningococcal meningitis. Eighty-seven of 99 (88%) eligible patients were included in the follow-up study; 46 (53%) were treated with dexamethasone and 41 (47%) with placebo. Median time between meningitis and testing was 99 months. Neuropsychological evaluation showed no significant differences between patients treated with dexamethasone and placebo. The proportions of patients with persisting neurological sequelae or hearing loss were similar in the dexamethasone and placebo groups. The overall rate of cognitive dysfunction did not differ significantly between patients and control subjects; however, patients after pneumococcal meningitis had a higher rate of cognitive dysfunction (21 vs 6%; p = 0.05) and experienced more impairment of everyday functioning due to physical problems (p = 0.05) than those after meningococcal meningitis. Treatment with adjunctive dexamethasone is not associated with an increased risk for long-term cognitive impairment. Adults who survive pneumococcal meningitis are at significant risk for long-term neuropsychological abnormalities.