Detection of anxiety symptoms and disorders in older adults: a diagnostic accuracy systematic review.

BACKGROUND: Anxiety symptoms and disorders are common in older adults and often go undetected. A systematic review was completed to identify tools that can be used to detect anxiety symptoms and disorders in community-dwelling older adults. METHODS: MEDLINE, Embase and PsycINFO were searched using the search concepts anxiety, older adults and diagnostic accuracy in March 2023. Included articles assessed anxiety in community-dwelling older adults using an index anxiety tool and a gold standard form of anxiety assessment and reported resulting diagnostic accuracy outcomes. Estimates of pooled diagnostic accuracy outcomes were completed. RESULTS: Twenty-three anxiety tools were identified from the 32 included articles. Pooled diagnostic accuracy outcomes were estimated for the Geriatric Anxiety Inventory (GAI)-20 [n = 3, sensitivity = 0.89, 95% confidence interval (CI) = 0.70-0.97, specificity = 0.80, 95% CI = 0.67-0.89] to detect generalized anxiety disorder (GAD) and for the GAI-20 (n = 3, cut off ≥ 9, sensitivity = 0.74, 95% CI = 0.62-0.83, specificity = 0.96, 95% CI = 0.74-1.00), Beck Anxiety Inventory (n = 3, sensitivity = 0.70, 95% CI = 0.58-0.79, specificity = 0.60, 95% CI = 0.51-0.68) and Hospital Anxiety and Depression Scale (HADS-A) (n = 3, sensitivity = 0.78, 95% CI = 0.60-0.89, specificity = 0.76, 95% CI = 0.60-0.87) to detect anxiety disorders in clinical samples. CONCLUSION: The GAI-20 was the most studied tool and had adequate sensitivity while maintaining acceptable specificity when identifying GAD and anxiety disorders. The GAI-20, GAI-Short Form and HADS-A tools are supported for use in detecting anxiety in community-dwelling older adults. Brief, self-rated and easy-to-use tools may be the best options for anxiety detection in community-dwelling older adults given resource limitations. Clinicians may consider factors including patient comorbidities and anxiety prevalence when selecting a tool and cut off.

Psychosis detection in dementia: a systematic review of diagnostic test accuracy studies.

Introduction: Symptoms of psychosis, characterized by delusions and hallucinations, are commonly experienced by persons living with dementia. A systematic review was completed to identify tools to evaluate symptoms of psychosis compared to a reference standard in persons with dementia. Articles reporting correlation values between psychosis tools were also identified. Methods: The search concepts psychosis, dementia, and diagnostic accuracy were used to search MEDLINE, PsycINFO, and Embase. Included articles meeting the primary objective described a tool to assess symptoms of psychosis, delusions, or hallucinations in persons with dementia, a reference standard form of diagnostic assessment for psychosis, and diagnostic accuracy outcomes for the psychosis tool. Secondary objective articles reported correlation values between two or more psychosis tools in persons with dementia. Results: One study met the primary objective and described the sensitivity and specificity of the Neuropsychiatric Inventory (NPI) and Columbia University Scale for Psychopathology in Alzheimer's Disease (CUSPAD) in identifying symptoms of psychosis, hallucinations, and delusions. The sensitivity of the NPI and CUSPAD in identifying symptoms of psychosis was 83 and 90%, respectively. Nine studies meeting the secondary objective described eleven unique tools and examined the degree to which tools used to assess psychotic symptoms in persons with dementia were related. Discussion: The NPI and CUSPAD were identified in a single study as psychosis tools that have been evaluated against a reference standard of psychosis assessment in persons with dementia. Various tools to assess the burden of psychotic symptoms in persons with dementia exist, but the diagnostic accuracy of existing tools remains understudied. Further research on the comparative utility and diagnostic accuracy is required for all psychosis tools used with persons with dementia.

Detecting agitation and aggression in persons living with dementia: a systematic review of diagnostic accuracy.

OBJECTIVE: 40-60% of persons living with dementia (PLWD) experience agitation and/or aggression symptoms. There is a need to understand the best method to detect agitation and/or aggression in PLWD. We aimed to identify agitation and/or aggression tools that are validated against a reference standard within the context of PLWD. METHODS: Our study was registered on PROSPERO (CRD42020156708). We searched MEDLINE, Embase, and PsycINFO up to April 22, 2024. There were no language or date restrictions. Studies were included if they used any tools or questionnaires for detecting either agitation or aggression compared to a reference standard among PLWD, or any studies that compared two or more agitation and/or aggression tools in the population. All screening and data extraction were done in duplicates. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Data extraction was completed in duplicates by two independent authors. We extracted demographic information, prevalence of agitation and/or aggression, and diagnostic accuracy measures. We also reported studies comparing the correlation between two or more agitation and/or aggression tools. RESULTS: 6961 articles were screened across databases. Six articles reporting diagnostic accuracy measures compared to a reference standard and 30 articles reporting correlation measurements between tools were included. The agitation domain of the Spanish NPI demonstrated the highest sensitivity (100%) against the agitation subsection of the Spanish CAMDEX. Single-study evidence was found for the diagnostic accuracy of commonly used agitation scales (BEHAVE-AD, NPI and CMAI). CONCLUSIONS: The agitation domain of the Spanish NPI, the NBRS, and the PAS demonstrated high sensitivities, and may be reasonable for clinical implementation. However, a limitation to this finding is that despite an extensive search, few studies with diagnostic accuracy measurements were identified. Ultimately, more research is needed to understand the diagnostic accuracy of agitation and/or aggression detection tools among PLWD.

Maternal postnatal depressive symptoms and early achievement of developmental milestones in infants and young children: A meta-analysis.

Screening for social determinants of health, including maternal depression, is a recommended pediatric practice. However, the magnitude of association between maternal and child screening tools remains to be determined. The current study evaluated the association between maternal postnatal depressive symptoms and child developmental milestones, as well as moderators of these associations. A comprehensive search strategy was carried out in four databases (MEDLINE, EMBASE, APA PsycINFO, and Cochrane Central Register of Controlled Trials) from database inception to September 2022. Studies that examine postnatal depressive symptoms and associations with infant and early child (<6 years) achievement of developmental milestones were included. Data were extracted by two independent coders and a random-effects meta-analysis was used to estimate pooled effect sizes and test for moderators. A total of 38 non-overlapping studies (95,897 participants), all focused on maternal postnatal depression, met inclusion criteria. The pooled effect size for the association between postnatal depressive symptoms and early achievement of infant and child developmental milestones (N = 38; r = -.12; 95% CI = -.18, -.06) was small in magnitude. Child age at maternal depression measurement was a moderator, whereby effect sizes became greater for older children. Despite small effects, maternal postnatal depressive symptoms should be included in screening during routine well-child visits to enhance child development outcomes.

El examinar los determinantes sociales de la salud, incluyendo la depresión materna, es una práctica pediátrica recomendada. Sin embargo, la magnitud de la asociación entre las herramientas de examinación materna y del niño está por ser determinada. El presente estudio evaluó la asociación entre los síntomas depresivos postnatales maternos y los momentos cruciales en el desarrollo del niño, así como su papel de moderadores de estas asociaciones. Una estrategia de investigación comprensiva se llevó a cabo en cuatro bancos de datos (MEDLINE, EMBASE, APA PsycINFO, y el Registro Central Cochrane para Ensayos Controlados) desde el inicio del banco de datos hasta septiembre de 2022. Se incluyeron los estudios que examinan los síntomas depresivos postnatales y sus asociaciones con el alcance de logros de momentos cruciales del infante y del niño en su temprana niñez (<6 años). Se extrajeron los datos por medio de dos independientes codificadores y se usó un metaanálisis de efectos al azar para estimar los tamaños de efectos agrupados y examinarlos como moderadores. Un total de 38 estudios que no compartían la misma información (95,897 participantes), todos enfocados en la depresión materna postnatal, reunieron los criterios para ser incluidos. El tamaño de los efectos agrupados para la asociación entre los síntomas depresivos postnatales y el logro temprano de los momentos cruciales del infante y el niño (N = 38; r = -.12; 95% CI = -.18, -.06) fue pequeño en magnitud. La edad del niño en la medida de la depresión materna fue un moderador, por lo cual los tamaños de los efectos se hicieron mayores para los niños de mayor edad. A pesar de los pequeños efectos, los síntomas depresivos postnatales maternos deben ser incluidos en la examinación durante las visitas rutinarias de chequeos del bienestar del niño para mejorar los resultados del desarrollo del niño.

Le dépistage de déterminants sociaux de la santé, y compris la dépression maternelle, est une pratique pédiatrique recommandée. Cependant la magnitude du lien entre les outils de dépistage maternelle et de l'enfant reste indéterminée. Cette étude a évalué le lien entre les symptômes dépressifs postnatals maternels et les jalons du développement de l'enfant, ainsi que les modérateurs de ces liens. Une stratégie de recherche exhaustive a été adoptée pour quatre bases de données (MEDLINE, EMBASE, APA PsycINFO, et Cochrane Central Register of Controlled Trials) des débuts de la base de données jusqu'à septembre 2022. Les études examinant les symptômes dépressifs postnatals et les liens avec l'atteinte des jalons de développement du nourrisson et du petit enfant (<6 ans) ont été inclues. Les données ont été extraites par deux codeurs et une méta-analyse à effets aléatoires a été utilisée afin d'estimer les tailles et tests d'effet regroupées pour les modérateurs. Un total de 38 études ne se recoupant pas (95897 participantes), toutes focalisées sur la dépression maternelle postnatale, ont rempli les critères d'inclusion. La taille d'effet regroupé pour le lien entre les symptômes dépressifs postnatales et l'atteinte précoce des jalons de développement du nourrisson et de l'enfant (N = 38; r = -,12; 95% CI = -,18, -,06) était petite en magnitude. L'âge de l'enfant à la mesure de la dépression maternelle était un modérateur, où l'ampleur de l'effet était plus grande pour les enfants plus âgés. En dépit du peu d'ampleur les symptômes dépressifs postnatals maternels devraient être inclus dans le dépistage durant les visites de routine de santé de l'enfant afin d'améliorer les résultats sur le développement de l'enfant.

The relationship of small vessel disease burden on cerebral and regional brain atrophy rates and cognitive performance over one year of follow-up after transient ischemic attack.

Background: Stroke, even when minor, increases the risk of dementia. We aimed to determine whether patients with transient ischaemic attack (TIA) exhibit higher rates of cerebral and regional atrophy 1-year after first stroke symptoms and evaluate the relationship with small vessel disease and cognitive performance. Methods: TIA patients and controls without cognitive symptoms underwent high-resolution T1-weighted MRI and cognitive testing at baseline and 1-year. Percent brain volume change (PBVC) was measured, and the location of regional atrophy and small vessel disease (CSVD) burden was evaluated. Neuropsychological testing assessed memory, processing speed, and executive function. Results: A total of 76 TIA patients and 53 controls of mean age 67 (SD = 8) and 68 years (SD = 8) were recruited. TIA patients demonstrated greater improvement of visual memory and executive function at 1-year. TIA patients had greater median PBVC/year compared to controls (-0.79% [(-1.22)-(-0.38)] vs. -0.41% [(-0.62)-0.19]; p < 0.001), and higher rates of volume loss (ml/year) in subcortical gray (-0.53 [(-1.09)-(-0.06)] vs. -0.13 [(-0.61)-0.31]; p < 0.05) and white matter (-2.21 [-5.47, 0.40] vs. -0.93 [(-3.43)-2.10]; p < 0.05). Linear regression showed that TIA, age, and systolic blood pressure (SBP) were associated with greater cerebral volume loss over 1-year. There was no significant relationship between PBVC and 1-year cognition. Conclusion: A near two-fold increase in rate of cerebral atrophy 1-year after TIA is associated with higher SBP emphasizing the need for improved treatment of SBP. Cerebral and regional atrophy rates may be used to select patients for vascular risk reduction trials or novel therapeutics in future dementia prevention trials.

Efficacy of virtual interventions for reducing symptoms of depression in community-dwelling older adults: a systematic review.

BACKGROUND: Older adults experience symptoms of depression, leading to suffering and increased morbidity and mortality. Although we have effective depression therapies, physical distancing and other public health measures have severely limited access to in-person interventions. OBJECTIVE: To describe the efficacy of virtual interventions for reducing symptoms of depression in community-dwelling older adults. DESIGN: Systematic review. SETTING: We searched MEDLINE, EMBASE, Cochrane Libraries, PsycINFO, and gray literature from inception to July 5, 2021. PARTICIPANTS AND INTERVENTIONS: We included randomized trials (RCTs) comparing the efficacy of virtual interventions to any other virtual intervention or usual care in community-dwelling adults ≥60 years old experiencing symptoms of depression or depression as an outcome. MEASUREMENTS: The primary outcome was change in symptoms of depression measured by any depression scale. RESULTS: We screened 12,290 abstracts and 830 full text papers. We included 15 RCTs (3100 participants). Five RCTs examined persons with depression symptoms at baseline and ten examined depression as an outcome only. Included studies demonstrated feasibility of interventions such as internet or telephone cognitive behavioral therapy with some papers showing statistically significant improvement in depressive symptoms. CONCLUSIONS: There is a paucity of studies examining virtual interventions in older adults with depression. Given difficulty in accessing in-person therapies in a pandemic and poor access for people living in rural and remote regions, there is an urgent need to explore efficacy, effectiveness, and implementation of virtual therapies.

Detecting depression in persons living in long-term care: a systematic review and meta-analysis of diagnostic test accuracy studies.

OBJECTIVE: Depressive disorders are common in long-term care (LTC), however, there is no one process used to detect depressive disorders in this setting. Our goal was to describe the diagnostic accuracy of depression detection tools used in LTC settings. METHODS: We conducted a systematic review and meta-analysis of diagnostic accuracy measures. The databases PubMed, EMBASE, PsycINFO and CINAHL were searched from inception to 10 September 2021. Studies involving persons living in LTC, assisted living residences or facilities, comparing diagnostic accuracy of depression tools with a reference standard, were included. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used to assess risk of bias. RESULTS: We identified 8,463 citations, of which 20 studies were included in qualitative synthesis and 19 in meta-analysis. We identified 23 depression detection tools (including different versions) that were validated against a reference standard. At a cut-off point of 6 on the Geriatric Depression Scale-15 (GDS-15), the pooled sensitivity was 73.6% (95% confidence interval (CI) 43.9%-76.5%), specificity was 76.5% (95% CI 62.9%-86.7%), and an area under the curve was 0.83. There was significant heterogeneity in these analyses. There was insufficient data to conduct meta-analysis of other screening tools. The Nursing Homes Short Depression Inventory (NH-SDI) had a sensitivity ranging from 40.0% to 98.0%. The 4-item Cornell Scale for Depression in Dementia (CSDD) had the highest sensitivity (67.0%-90.0%) for persons in LTC living with dementia. CONCLUSIONS: There are 23 tools validated for detection of depressive disorders in LTC, with the GDS-15 being the most studied. Tools developed specifically for use in LTC settings include the NH-SDI and CSDD-4, which provide briefer options to screen for depression. However, more studies of both are needed to examine tool accuracy using meta-analyses.

A Randomized Controlled Trial of Tai Chi Chih or Health Education for Geriatric Depression.

OBJECTIVES: Geriatric depression is difficult to treat and frequently accompanied by treatment resistance, suicidal ideations and polypharmacy. New adjunctive mind-body treatment strategies can improve clinical outcomes in geriatric depression and reduce risk for side-effects of pharmacological treatments. METHODS: We conducted a 3-month randomized controlled trial to assess the efficacy and tolerability of combining Tai Chi Chih (TCC) or Health Education and Wellness training (HEW) with the stable standard antidepressant treatment on mood and cognitive functioning in depressed older adults (NCT02460666). Primary outcome was change in depression as assessed by the Hamilton Rating Scale for Depression (HAM-D) post-treatment. Remission was defined as HAM-D ≤ 6; naturalistic follow-up continued for 6 months. We also assessed psychological resilience, health-related quality of life and cognition. RESULTS: Of the 178 randomized participants, 125 completed the 3-month assessment and 117 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Remission rate within TCC was 35.5% and 33.3%, compared to 27.0% and 45.8% in HEW, at 3 and 6 months respectively (χ2(1) = 1.0, p = 0.3; χ2(1) = 1.9, p =0.2). Both groups improved significantly on the HAM-D at 3 and 6 months. TCC demonstrated a greater improvement in general health compared to HEW. CONCLUSIONS: Both TCC and HEW combined with a standard antidepressant treatment improved symptoms of depression in older adults. While TCC was superior to HEW in improving general health, we did not find group differences in improvement in mood and cognition.

Hippocampal atrophy and cognitive function in transient ischemic attack and minor stroke patients over three years.

Introduction: Transient ischemic attack (TIA) and minor ischemic stroke (IS) is associated with a increased risk of late life dementia. In this study we aim to study the extent to which the rates of hippocampal atrophy in TIA/IS differ from healthy controls, and how they are correlated to neuropsychological measurements. Methods: TIA or minor stroke patients were tested with a neuropsychological battery including tests of executive function, and verbal and non-verbal memory at three time points out to 3 years. Annualized rates of hippocampal atrophy in TIA/IS patients were compared to controls. A linear-mixed regression model was used to assess the difference in rates of hippocampal atrophy after adjusting for time and demographic characteristics. Results: TIA/IS patients demonstrated a higher hippocampal atrophy rate than healthy controls over a 3-year interval: the annual percentage change of the left hippocampal volume was 2.5% (78 mm3 per year (SD 60)) for TIA/IS patients compared to 0.9% (29 mm3 per year (SD 32)) for controls (p < 0.01); and the annual percentage change of the right hippocampal volume was 2.5% (80 mm3 per year (SD 46)) for TIA/IS patients compared to 0.5% (17 mm3 per year (SD 33)) for controls (P < 0.01). Patients with higher annual hippocampal atrophy were more likely to report higher TMT B times, but lower ROC total score, lower California Verbal Learning Test-II total recall, and lower ROC Figure recall scores longitudinally. Conclusion: TIA/IS patients experience a higher rate of hippocampal atrophy independent of TIA/IS recurrence that are associated with changes in episodic memory and executive function over 3 years.

A Randomized Double-Blind Placebo-Controlled Trial of Combined Escitalopram and Memantine for Older Adults With Major Depression and Subjective Memory Complaints.

OBJECTIVE: Geriatric depression is difficult to treat and frequently accompanied by cognitive complaints that increase risk for dementia. New treatment strategies targeting both depression and cognition are urgently needed. METHODS: We conducted a 6-month double-blind placebo-controlled trial to assess the efficacy and tolerability of escitalopram + memantine (ESC/MEM) compared to escitalopram + placebo (ESC/PBO) for improving mood and cognitive functioning in depressed older adults with subjective memory complaints (NCT01902004). Primary outcome was change in depression as assessed by the HAM-D post-treatment (at 6 months). Remission was defined as HAM-D ≤6; naturalistic follow-up continued until 12 months. RESULTS: Of the 95 randomized participants, 62 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Mean daily escitalopram dose was 11.1 mg (SD = 3.7; range: 5-20 mg). Mean daily memantine dose was 19.3 mg (SD = 2.6; range 10-20 mg). Remission rate within ESC/MEM was 45.8% and 47.9%, compared to 38.3% and 31.9% in ESC/PBO, at 3 and 6 months, respectively (χ2(1) = 2.0, p = 0.15). Both groups improved significantly on the HAM-D at 3, 6, and 12 months, with no observed between-group differences. ESC/MEM demonstrated greater improvement in delayed recall (F(2,82) = 4.3, p = 0.02) and executive functioning (F(2,82) = 5.1, p = 0.01) at 12 months compared to ESC/PBO. CONCLUSIONS: The combination of memantine with escitalopram was well tolerated and as effective as escitalopram and placebo in improving depression using HAM-D. Combination memantine and escitalopram was significantly more effective than escitalopram and placebo in improving cognitive outcomes at 12 months. Future reports will address the role of biomarkers of aging in treatment response.

Health-Promoting Strategies for the Aging Brain.

As the world's population ages and people live longer, the changes in the aging brain present substantial challenges to our health and society. With greater longevity come age-related diseases, many of which have direct and indirect influences on the health of the brain. Although there is some degree of predictable decline in brain functioning with aging, meaningful cognitive decline is not inevitable and is perhaps preventable. In this review, we present the case that the course of aging-related brain disease and dysfunction can be modified. We present the evidence for conditions and risk factors that may contribute to cognitive decline and dementia and for interventions that may mitigate their impact on cognitive functioning later in life, or even prevent them and their cognitive sequelae from developing. Although much work remains to be done to meet the challenges of the aging brain, strategies to promote its health have been demonstrated and offer much promise, which can only be realized if we mount a vigorous public health effort to implement these strategies.

Neurocognitive Correlates of Resilience in Late-Life Depression.

OBJECTIVE: Increasing understanding of the neurocognitive correlates of resilience in late-life depression (LLD) could inform interventions to promote more sustained remission. We investigated cross-sectional relations between baseline resilience and domains of neurocognitive functioning in depressed older adults enrolled in one of four trials. METHODS: Participants (N = 288) completed neurocognitive tests of memory, language performance, and executive functioning as well as measures of subjective memory performance and components of resilience (grit, active coping self-efficacy, accommodative coping self-efficacy, and spirituality). RESULTS: Medium-sized associations were observed between greater resilience (overall resilience, accommodative coping) and lower frequency of self-reported forgetting. Small positive associations were observed between language performance and total resilience, active coping self-efficacy, and accommodative coping self-efficacy. Small negative associations were observed between spirituality and each objective measure of cognitive performance. CONCLUSION: Future longitudinal studies will help elucidate the complex relation between resilience and cognitive functioning in LLD. In addition, randomized controlled trials targeting coping self-efficacy may inform the development of more effective and personalized interventions.

Simultaneous Aerobic Exercise and Memory Training Program in Older Adults with Subjective Memory Impairments.

BACKGROUND: Several modifiable lifestyle factors have been shown to have potential beneficial effects in slowing cognitive decline. Two such factors that may affect cognitive performance and slow the progression of memory loss into dementia in older adults are cognitive training and physical activity. There are currently no effective treatments for dementia; therefore, preventative strategies to delay or prevent the onset of dementia are of critical importance. OBJECTIVE: The aim of this study was to determine the relative effectiveness of simultaneous performance of memory training and aerobic exercise to a sequential performance intervention on memory functioning in older adults. METHODS: 55 older adults (aged 60- 75) with subjective memory impairments (non-demented and non-MCI) completed the intervention that consisted of 90-minute small group classes held twice weekly. Participants were randomized to either 4-weeks of supervised strategy-based memory training done simultaneously while stationary cycling (SIM) or sequentially after the stationary cycling (SEQ). Standardized neurocognitive measures of memory, executive functioning, speed of processing, attention, and cognitive flexibility were assessed at baseline and post-intervention. RESULTS: The SIM group, but not the SEQ group, had a significant improvement on composite memory following the intervention (t(51) = 2.7, p = 0.01, effect size (ES) = 0.42) and transfer to non-trained reasoning abilities (t(51) = 6.0, ES = 0.49) and complex attention (t(51) = 3.1, p = 0.003, ES = 0.70). Conversely, the SEQ group, but not the SIM, showed significant improvement in executive functioning (t(51) = 5.0, p = 0.0001, ES = 0.96). CONCLUSION: These findings indicate that a 4-week simultaneous memory training and aerobic exercise program is sufficient to improve memory, attention, and reasoning abilities in older adults.

CRLX101, a Nanoparticle-Drug Conjugate Containing Camptothecin, Improves Rectal Cancer Chemoradiotherapy by Inhibiting DNA Repair and HIF1α.

Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of CRLX101, an investigational nanoparticle-drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. CRLX101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. CRLX101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of CRLX101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, CRLX101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with CRLX101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for CRLX101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for CRLX101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 NCT02010567). Cancer Res; 77(1); 112-22. ©2016 AACR.

Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice.

OBJECTIVE: To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS). METHODS: NanoString microRNA, microglia and immune gene profiles, protein mass spectrometry, and RNA-seq analyses were measured in spinal cord microglia, splenic monocytes, and spinal cord tissue from SOD1 mice and in spinal cord tissue of familial and sporadic ALS. miR-155 was targeted by genetic ablation or by peripheral or centrally administered anti-miR-155 inhibitor in SOD1 mice. RESULTS: In SOD1 mice, we found loss of the molecular signature that characterizes homeostatic microglia and increased expression of miR-155. There was loss of the microglial molecules P2ry12, Tmem119, Olfml3, transcription factors Egr1, Atf3, Jun, Fos, and Mafb, and the upstream regulators Csf1r, Tgfb1, and Tgfbr1, which are essential for microglial survival. Microglia biological functions were suppressed including phagocytosis. Genetic ablation of miR-155 increased survival in SOD1 mice by 51 days in females and 27 days in males and restored the abnormal microglia and monocyte molecular signatures. Disease severity in SOD1 males was associated with early upregulation of inflammatory genes, including Apoe in microglia. Treatment of adult microglia with apolipoprotein E suppressed the M0-homeostatic unique microglia signature and induced an M1-like phenotype. miR-155 expression was increased in the spinal cord of both familial and sporadic ALS. Dysregulated proteins that we identified in human ALS spinal cord were restored in SOD1(G93A) /miR-155(-/-) mice. Intraventricular anti-miR-155 treatment derepressed microglial miR-155 targeted genes, and peripheral anti-miR-155 treatment prolonged survival. INTERPRETATION: We found overexpression of miR-155 in the SOD1 mouse and in both sporadic and familial human ALS. Targeting miR-155 in SOD1 mice restores dysfunctional microglia and ameliorates disease. These findings identify miR-155 as a therapeutic target for the treatment of ALS.

Differential roles of microglia and monocytes in the inflamed central nervous system.

In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.

Identification of a unique TGF-ß-dependent molecular and functional signature in microglia.

Microglia are myeloid cells of the CNS that participate both in normal CNS function and in disease. We investigated the molecular signature of microglia and identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia versus myeloid and other immune cells. Of the 239 genes, 106 were enriched in microglia as compared with astrocytes, oligodendrocytes and neurons. This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS, and was also observed in human microglia. We found that TGF-ß was required for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia and that microglia were absent in the CNS of TGF-ß1-deficient mice. Our results identify a unique microglial signature that is dependent on TGF-ß signaling and provide insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.

Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with neuronal cell death that is thought to involve aberrant immune responses. Here we investigated the role of innate immunity in a mouse model of ALS. We found that inflammatory monocytes were activated and that their progressive recruitment to the spinal cord, but not brain, correlated with neuronal loss. We also found a decrease in resident microglia in the spinal cord with disease progression. Prior to disease onset, splenic Ly6Chi monocytes expressed a polarized macrophage phenotype (M1 signature), which included increased levels of chemokine receptor CCR2. As disease onset neared, microglia expressed increased CCL2 and other chemotaxis-associated molecules, which led to the recruitment of monocytes to the CNS by spinal cord-derived microglia. Treatment with anti-Ly6C mAb modulated the Ly6Chi monocyte cytokine profile, reduced monocyte recruitment to the spinal cord, diminished neuronal loss, and extended survival. In humans with ALS, the analogous monocytes (CD14+CD16-) exhibited an ALS-specific microRNA inflammatory signature similar to that observed in the ALS mouse model, linking the animal model and the human disease. Thus, the profile of monocytes in ALS patients may serve as a biomarker for disease stage or progression. Our results suggest that recruitment of inflammatory monocytes plays an important role in disease progression and that modulation of these cells is a potential therapeutic approach.

Advance care planning among the oldest old.

OBJECTIVES: To describe end-of-life advance care planning among the oldest-old (those >/= 85 years) and to identify patient characteristics and healthcare utilization patterns associated with likelihood of care planning documentation. DESIGN: Medical charts were abstracted for evidence of advance care planning documentation (including surrogate for health care decisions) and linked to patient demographic, clinical, and health utilization characteristics. SETTING: Veterans Affairs Greater Los Angeles Healthcare System (VA GLAHS). PARTICIPANTS: All Veterans (n = 175) aged >/= 85 who died between September 1999 and October 2000 and used services at the VA GLAHS in the last year of life. MEASUREMENTS: The association of patient demographic, clinical, and health care utilization characteristics with documentation of advance care planning and surrogates was modeled using multivariate logistic regression. RESULTS: Among veterans (mean age at death, 89.4 +/- 3.8 years), 50 of 149 (34%) electronic available records had documented care preferences whereas 68 (46%) had documentation of surrogates. Considering demographic, clinical, and service use characteristics, only age (adjusted odds ratio [AOR]: 1.1 per year; 95% confidence interval [CI]: 1.0-1.2) and outpatient visits (AOR: 1.6 per quartile of general and geriatric medicine visit frequency; 95% CI: 1.1-;2.3) were associated with advance directive completion. A multivariable regression model using the same predictors to predict documentation of surrogates found similar associations with total outpatient visits (AOR: 1.5; 95% CI: 1.0-2.0) and general and geriatric medicine utilization. (AOR: 1.4; 95% CI: 1.0-2.0). CONCLUSION: Even in a health care system known for high-quality chronic illness care, documentation of advance care planning and selected proxies for health care decisions at the end of life was infrequent. Outpatient primary care and geriatric providers' visits were more frequent among those who had documented advance care planning, suggesting that involvement of these practitioners may improve end-of-life care.