A role for norepinephrine in learning and memory has been elusive and controversial. A longstanding hypothesis states that the adrenergic nervous system mediates enhanced memory consolidation of emotional events. We tested this hypothesis in several learning tasks using mutant mice conditionally lacking norepinephrine and epinephrine, as well as control mice and rats treated with adrenergic receptor agonists and antagonists. We find that adrenergic signaling is critical for the retrieval of intermediate-term contextual and spatial memories, but is not necessary for the retrieval or consolidation of emotional memories in general. The role of norepinephrine in retrieval requires signaling through the beta(1)-adrenergic receptor in the hippocampus. The results demonstrate that mechanisms of memory retrieval can vary over time and can be different from those required for acquisition or consolidation. These findings may be relevant to symptoms in several neuropsychiatric disorders as well as the treatment of cardiac failure with beta blockers.

IMPORTANCECognitive impairment and dementia, including Alzheimer disease (AD), are common within the aging population, yet the factors that render the aging brain vulnerable to these processes are unknown. Perivascular localization of aquaporin-4 (AQP4) facilitates the clearance of interstitial solutes, including amyloid-β, through the brainwide network of perivascular pathways termed the glymphatic system, which may be compromised in the aging brain.OBJECTIVES To determine whether alterations in AQP4 expression or loss of perivascular AQP4 localization are features of the aging human brain and to define their association with AD pathology. DESIGN, SETTING, AND PARTICIPANTS Expression of AQP4 was analyzed in postmortem frontal cortex of cognitively healthy and histopathologically confirmed individuals with AD byWestern blot or immunofluorescence for AQP4, amyloid-β 1-42, and glial fibrillary acidic protein. Postmortem tissue and clinical data were provided by the Oregon Health and Science University Layton Aging and Alzheimer Disease Center and Oregon Brain Bank. Postmortem tissue from 79 individuals was evaluated, including cognitively intact "young" individuals aged younger than 60 years (range, 33-57 years), cognitively intact "aged" individuals aged older than 60 years (range, 61-96 years) with no known neurological disease, and individuals older than 60 years (range, 61-105 years) of age with a clinical history of AD confirmed by histopathological evaluation. Forty-eight patient samples (10 young, 20 aged, and 18 with AD) underwent histological analysis. Sixty patient samples underwent Western blot analysis (15 young, 24 aged, and 21 with AD).MAIN OUTCOMES AND MEASURES Expression of AQP4 protein, AQP4 immunoreactivity, and perivascular AQP4 localization in the frontal cortex were evaluated. RESULTSExpression of AQP4 was associated with advancing age among all individuals (R 2 = 0.17; P = .003). Perivascular AQP4 localization was significantly associated with AD status independent of age (OR, 11.7 per 10% increase in localization; z = −2.89; P = .004) and was preserved among eldest individuals older than 85 years of age who remained cognitively intact. When controlling for age, loss of perivascular AQP4 localization was associated with increased amyloid-β burden (R 2 = 0.15; P = .003) and increasing Braak stage (R 2 = 0.14; P = .006). CONCLUSIONS AND RELEVANCEIn this study, altered AQP4 expression was associated with aging brains. Loss of perivascular AQP4 localization may be a factor that renders the aging brain vulnerable to the misaggregation of proteins, such as amyloid-β, in neurodegenerative conditions such as AD.

Significance Failure of the host immune system to control infection with Mycobacterium tuberculosis is a major determinant of tuberculosis (TB) disease. In this work, we examined the role of macrophage migration inhibitory factor (MIF), a cytokine that is encoded in a functionally polymorphic locus in humans, in TB. We found genetic low expressers of MIF to be enriched in a population of patients with HIV and disseminated TB. From our work in cellular and mouse models, we propose a key mechanism by which MIF regulates bacterial recognition as the first step in triggering inflammatory pathways to enable mycobacterial control.

Acupuncture is beneficial in some peripheral neuropathies, but more rigorously designed studies using sham-acupuncture control are needed to characterize its effect and optimal use better.

While a very-low fat, plant-based diet was well adhered to and tolerated, it resulted in no significant improvement on brain MRI, relapse rate or disability as assessed by EDSS scores in subjects with RRMS over one year. The diet group however showed significant improvements in measures of fatigue, BMI and metabolic biomarkers. The study was powered to detect only very large effects on MRI activity so smaller but clinically meaningful effects cannot be excluded. The diet intervention resulted in a beneficial effect on the self-reported outcome of fatigue but these results should be interpreted cautiously as a wait-list control group may not completely control for a placebo effect and there was a baseline imbalance on fatigue scores between the groups. If maintained, the improved lipid profile and BMI could yield long-term vascular health benefits. Longer studies with larger sample sizes are needed to better understand the long-term health benefits of this diet.

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This study provides Class III evidence that for patients with PD undergoing DBS, asleep intraoperative CT imaging-guided implantation is not significantly different from awake microelectrode recording-guided implantation in improving motor outcomes at 6 months.

Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn−/− mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing.