BackgroundStroke, 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.MethodsTIA 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.ResultsA 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.ConclusionA 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.

Oral Presentations Theme 1: Applied Sciences and Interventions for Brain Health and Dementia ABSTRACT #1: Novel peptide aptamers as potential therapeutic candidates for the treatment of Alzheimer’s disease Tahir Ali (1, 2), Antonia N. Klein (1, 3), Alex Vu (1, 2), and Sabine Gilch (1, 2)1: Novel peptide aptamers as potential therapeutic candidates for the treatment of Alzheimer’s disease Tahir Ali (1, 2), Antonia N. Klein (1, 3), Alex Vu (1, 2), and Sabine Gilch (1, 2) 1Calgary Prion Research Unit, Department of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada 2Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta,

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.

This article has been removed: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal)This meeting abstract has been removed by the Publisher. Due to an administrative error, abstracts that were not presented at the ISDN 2014 meeting were inadvertently published in the meeting's abstract supplement. The Publisher apologizes to the authors and readers for this error.

This article has been removed: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal)This meeting abstract has been removed by the Publisher. Due to an administrative error, abstracts that were not presented at the ISDN 2014 meeting were inadvertently published in the meeting's abstract supplement. The Publisher apologizes to the authors and readers for this error.

This article has been removed: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our‐business/policies/article‐withdrawal)This meeting abstract has been removed by the Publisher. Due to an administrative error, abstracts that were not presented at the ISDN 2014 meeting were inadvertently published in the meeting's abstract supplement. The Publisher apologizes to the authors and readers for this error.

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.

Nat. Neurosci. 17, 131–143 (2014); published online 8 December 2013; corrected after print 19 December 2013 In the version of this article initially published, the x-axis labels for the sets of graphs in Figure 2f corresponding to astrocyte, oligodendrocyte and neuron molecules consisted of six items, even though there were only five bars.

Nat. Neurosci. 17, 131–143 (2014); published online 8 December 2013; corrected after print 19 December 2013 In the version of this article initially published, the x-axis labels for the sets of graphs in Figure 2f corresponding to astrocyte, oligodendrocyte and neuron molecules consisted of six items, even though there were only five bars.

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.

OBJECTIVE: To identify a unique signature of murine and human microglia.

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.