Point-of-Care Ultrasound to Detect Acute Large Vessel Occlusions in Stroke Patients: A Proof-of-Concept Study.

BACKGROUND AND PURPOSE: A primary admission of patients with suspected acute ischemic stroke and large vessel occlusion (LVO) to centers capable of providing endovascular stroke therapy (EVT) may induce shorter time to treatment and better functional outcomes. One of the limitations in this strategy is the need for accurately identifying LVO patients in the prehospital setting. We aimed to study the feasibility and diagnostic performance of point-of-care ultrasound (POCUS) for the detection of LVO in patients with acute stroke. METHODS: We conducted a proof-of-concept study and selected 15 acute ischemic stroke patients with angiographically confirmed LVO and 15 patients without LVO. Duplex ultrasonography (DUS) of the common carotid arteries was performed, and flow profiles compatible with LVO were scored independently by one experienced and one junior neurologist. RESULTS: Among the 15 patients with LVO, 6 patients presented with an occlusion of the carotid-T and 9 patients presented with an M1 occlusion. Interobserver agreement between the junior and the experienced neurologist was excellent (kappa = 0.813, p < 0.001). Flow profiles of the CAA allowed the detection of LVO with a sensitivity of 73%, a positive predictive value of 92 and 100%, and a c-statistics of 0.83 (95%CI = 0.65-0.94) and 0.87 (95%CI = 0.69-0.94) (experienced neurologist and junior neurologist, respectively). In comparison with clinical stroke scales, DUS was associated with better trade-off between sensitivity and specificity. CONCLUSION: POCUS in acute stroke setting is feasible, it may serve as a complementary tool for the detection of LVO and is potentially applicable in the prehospital phase.

Apathy in patients with Alzheimer's disease is a cost-driving factor.

BACKGROUND: Apathy is the most frequent neuropsychiatric symptom in patients with dementia of the Alzheimer's type (DAT). We analyzed the influence of apathy on the resource use of DAT patients and their caregivers. METHODS: Included were baseline data of 107 DAT patients from a randomized clinical trial on apathy treatment. The Resource Utilization in Dementia (RUD) instrument assessed costs over a 1-month period prior to baseline. Cost predictors were determined via a least absolute shrinkage and selection operator (LASSO). RESULTS: On average, total monthly costs were €3070, of which €2711 accounted for caregivers' and €359 for patients' costs. An increase of one point in the Apathy Evaluation Scale resulted in a 4.1% increase in total costs. DISCUSSION: Apathy is a significant cost driving factor for total costs in mild to moderate DAT. Effective treatment of apathy might be associated with reduced overall costs in DAT.

α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid ß1-42-stimulated murine astrocytes.

BACKGROUND: Neuroinflammation has an essential impact on the pathogenesis and progression of Alzheimer's disease (AD). Mostly mediated by microglia and astrocytes, inflammatory processes lead to degeneration of neuronal cells. The NLRP3-inflammasome (NOD-like receptor family, pyrin domain containing 3) is a key component of the innate immune system and its activation results in secretion of the proinflammatory effectors interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). Under physiological conditions, cytosolic NLRP3-inflammsome is maintained in an inactive form, not able to oligomerize. Amyloid ß1-42 (Aß1-42) triggers activation of NLRP3-inflammasome in microglia and astrocytes, inducing oligomerization and thus recruitment of proinflammatory proteases. NLRP3-inflammasome was found highly expressed in human brains diagnosed with AD. Moreover, NLRP3-deficient mice carrying mutations associated with familial AD were partially protected from deficits associated with AD. The endogenous protease inhibitor α1-antitrypsin (A1AT) is known for its anti-inflammatory and anti-apoptotic properties and thus could serve as therapeutic agent for NLRP3-inhibition. A1AT protects neurons from glutamate-induced toxicity and reduces Aß1-42-induced inflammation in microglial cells. In this study, we investigated the effect of Aß1-42-induced NLRP3-inflammasome upregulation in primary murine astrocytes and its regulation by A1AT. METHODS: Primary cortical astrocytes from BALB/c mice were stimulated with Aß1-42 and treated with A1AT. Regulation of NLRP3-inflammasome was examined by immunocytochemistry, PCR, western blot and ELISA. Our studies included an inhibitor of NLRP3 to elucidate direct interactions between A1AT and NLRP3-inflammasome components. RESULTS: Our study revealed that A1AT reduces Aß1-42-dependent upregulation of NLRP3 at the mRNA and protein levels. Furthermore, A1AT time-dependently mitigated the expression of caspase 1 and its cleavage product IL-1ß in Aß1-42-stimulated astrocytes. CONCLUSION: We conclude that Aß1-42-stimulation results in an upregulation of NLRP3, caspase 1, and its cleavage products in astrocytes. A1AT time-dependently hampers neuroinflammation by downregulation of Aß1-42-mediated NLRP3-inflammasome expression and thus may serve as a pharmaceutical opportunity for the treatment of Alzheimer's disease.

Modern Interdisciplinary and Interhospital Acute Stroke Therapy-What Patients Think About It and What They Really Understand.

BACKGROUND: Access to reperfusion therapies in patients with large vessel occluding acute ischemic stroke demands process reorganization and optimization. Neurovascular networks are being built up to provide 24/7 endovascular stroke therapy service. In times of an increasingly complex stroke rescue chain little is known about patients' and their relatives' treatment awareness. METHODS: All patients, who received any kind of acute reperfusion treatment between January and August 2017 in the university hospital Aachen, and their proxies, were included in the survey. Patients were either primarily or secondarily transferred. RESULTS: For all questions regarding stroke treatment patients and their caregivers provided concurring answers. 40% of both patients and caregivers did not understand the treatment that was performed. Finally, patients who perceived on their own that stroke detection was delayed had significantly longer onset to door times than patients who did not have this impression. CONCLUSIONS: This study showed that patients' and proxies' answers correlated significantly. In case of patients' unavailability extrapolation of treatment satisfaction from answers by proxies might be permitted. High percentages of patients and caregivers do not understand relevant information, possibly due to limits of communication in an emergency setting or deficits in communication during the hospital stay. More emphasis should be laid on providing further information during the hospital stay.

Transfer of stroke patients impairs eligibility for endovascular stroke treatment.

BACKGROUND: Many patients who are potentially eligible for endovascular stroke treatment (EST) receive intravenous rtPA in the closest stroke unit before being transferred to tertiary centres for EST. It has been shown that clinical outcome of transferred and EST-treated patients is comparable to that of patients with direct access to EST. We analysed clinical outcome of patients, who were transferred and eventually not treated due to clinical and/or radiological deterioration. METHODS: We retrospectively analysed our prospectively maintained stroke registry for patients who were transferred for stroke therapy. RESULTS: Four hundred twenty-two of 1208 patients (35.1%), who were admitted for acute reperfusion stroke therapy between 03/10 and 01/15 were eligible for EST. Ninety-one (7.5%) of these patients were admitted specifically for EST from remote hospitals. Favorable clinical outcome rates after 90 days (mRS≤2) were comparable between 63 transferred and 295 directly-admitted patients, who received EST (P=0.699). However, transferred patients, who were eligible for EST on initial admission, were less likely to receive EST after transfer (P<0.001): twenty-two of 91 patients (24.2%), who were transferred for EST, became ineligible during transfer due to infarct demarcation. Procedural times of treated and untreated transferred patients were comparable (P≥0.508). There was a trend towards worse clinical outcome in untreated patients, without reaching statistical significance (OR, 0.269; 95% CI, 0.55-1.324; P=0.119). CONCLUSIONS: EST should be provided directly whenever possible as one in four transferred stroke patients becomes ineligible for EST during transfer. If direct transfer is not possible, indication for EST should be re-assessed after transfer.

Vaccination strategies in tauopathies and synucleinopathies.

Vaccination therapies constitute potential treatment options in neurodegenerative disorders such as Alzheimer disease or Parkinson disease. While a lot of research has been performed on vaccination against extracellular amyloid ß, the focus recently shifted toward vaccination against the intracellular proteins tau and α-synuclein, with promising results in terms of protein accumulation reduction. In this review, we briefly summarize lessons to be learned from clinical vaccination trials in Alzheimer disease that target amyloid ß. We then focus on tau and α-synuclein. For both proteins, we provide important data on protein immunogenicity, and put them into context with data available from both animals and human vaccination trials targeted at tau and α-synuclein. Together, we give a comprehensive overview about current clinical data, and discuss associated problems.

Anterior sacral meningocele infected with Fusobacterium in a patient with recently diagnosed colorectal carcinoma - a case report.

BACKGROUND: Anterior sacral meningoceles are rare, and usually occur with other malformations of the posterior lower spine. While these are more frequently reported in pediatric cohorts, we report a case in an elderly woman. CASE PRESENTATION: We report on a 71 year-old woman with a recently diagnosed colorectal adenocarcinoma who presented with a severe bacterial meningitis. The cerebrospinal fluid cell count revealed a pleocytosis of 80,000 cells/µl and a severe disturbance of the blood-brain-barrier. Fusobacterium nucleatum was cultured as the causing pathogen. A lumbar MRI showed, in addition to contrast-enhancing meninges as sign of inflammation, a presacral mass. In the next step, the mass was diagnosed as an anterior sacral meningocele connected to the gut. An adequate antibiotic was used to treat the leptomeningitis. The connection between gut and meningocele was closed surgically and the patient recovered well and underwent further treatment of her colorectal adenocarcinoma. CONCLUSION: We report on a case of meningitis with an anterior sacral meningocele that was connected to the gut in a patient with a infiltrative colorectal adenocarcinoma. Anatomic variants have to be considered as rare causes of meningitis with typical intestinal germs.

Mortality and cardiorespiratory complications in trochanteric femoral fractures: a ten year retrospective analysis.

PURPOSE: Despite intense research and innovations in peri-operative management, a high mortality rate and frequent systemic complications in trochanteric femoral fractures persist. The aim of the present study was to identify predictive factors for mortality and cardio-respiratory complications after different treatment methods in a ten year period at a level I trauma centre. METHODS: Retrospectively, all patients above 60 years of age with trochanteric femoral fracture between January 2000 and May 2011 were analyzed at a level I trauma centre. Demographic variables, comorbidities, and data regarding the surgical procedures, including required transfusions and post-operative complications, were evaluated, and the in-hospital mortality was recorded. The grade of osteoporosis was classified radiographically using the Singh index. RESULTS: The in-hospital mortality rate was 8.2% among 437 patients (male/female ratio = 110/327, mean age = 81 years) with extramedullary open (n = 144), intramedullary (n = 166), and extramedullary minimally invasive (n = 125) procedures. Significant influential factors on in-hospital mortality were identified with binary logistic regression analysis: an age of ≥90 years (P = 0.011), male sex (P = 0.003), a high American Society of Anesthesiologists (ASA) grade (3-5, P = 0.042), and a high osteoporosis grade (Singh index 3-1, P = 0.011). A total of 21.5% of the study population suffered cardio-respiratory complications post-operatively. The specific mortality was 28.7% (P < 0.001), which was influenced by a high ASA grade (3-5, P = 0.002) and a high transfusion rate (P = 0.004). Minimally invasive locked plating was associated with increased cardio-respiratory complications (P = 0.031). CONCLUSIONS: This study identified high patient age, distinctive comorbidities, male sex, and high osteoporosis grade as significant risk factors for increased in-hospital mortality in the treatment of trochanteric femoral fractures. Furthermore, high ASA grade and a liberal transfusion regime led to an increased incidence of cardio-respiratory complications. Patient-specific characteristics, especially osteoporosis grade and pre-existing medical conditions, may assist in the identification of high-risk patients and allow a patient-specific geriatric co-management plan.

Pathogenic and physiological autoantibodies in the central nervous system.

In this article, we review the current knowledge on pathological and physiological autoantibodies directed toward structures in the central nervous system (CNS) with an emphasis on their regulation and origin. Pathological autoantibodies in the CNS that are associated with autoimmunity often lead to severe neurological deficits via inflammatory processes such as encephalitis. In some instances, however, autoantibodies function as a marker for diagnostic purposes without contributing to the pathological process and/or disease progression. The existence of naturally occurring physiological autoantibodies has been known for a long time, and their role in maintaining homeostasis is well established. Within the brain, naturally occurring autoantibodies targeting aggregated proteins have been detected and might be promising candidates for new therapeutic approaches for neurodegenerative disorders. Further evidence has demonstrated the existence of naturally occurring antibodies targeting antigens on neurons and oligodendrocytes that promote axonal outgrowth and remyelination. The numerous actions of physiological autoantibodies as well as their regulation and origin are summarized in this review.

α1-antitrypsin modulates microglial-mediated neuroinflammation and protects microglial cells from amyloid-ß-induced toxicity.

BACKGROUND: One hallmark of Alzheimer disease is microglial activation. Therapeutic approaches for this neurodegenerative disease include the modulation of microglial cells. α1-antitrypsin (A1AT) has been shown to exert anti-inflammatory effects on macrophages and lung epithelial cells and an inhibition of calpain activity in neutrophil granulocytes. Nothing is known about the effect of A1AT on microglial-mediated neuroinflammation. Our aim was to investigate the effect of A1AT on amyloid-ß (Aß)- and LPS-treated microglial cells in vitro with respect to cytokine production, stress pathways, cell viability, phagocytotic abilities and the underlying mechanisms. METHODS: Primary microglial cells were isolated from Swiss Webster mouse embryos on embryonic day 13.5. Cytokines in the supernatants of treated primary microglial cells were analyzed with ELISAs, and accumulated nitrite was detected with Griess reagents. Intracellular stress pathways were investigated in cell lysates using western blotting. Intracellular calcium levels were detected in BV-2 microglial cells loaded with the Ca2+-sensitive (fluorescent) dye Fluo-4. Calpain activity in primary microglial cells was assessed by using a calpain activity assay. Cell viability of Aß-treated microglial cells was analyzed using MTT assay. Phagocytosis of Aß was evaluated with western blot analysis. RESULTS: Upon co-administration, A1AT reduced pro-inflammatory mediators induced by LPS or Aß. Interestingly, we detected a reduction in calpain activity and in the concentration of intracellular calcium that might mediate the anti-inflammatory effects of A1AT. Inhibition of the classic activation pathways, such as phosphorylation of mitogen-activated protein kinases or activation of protein kinase A were excluded as a mechanism of A1AT-mediated effects. In addition, A1AT increased the viability of Aß-treated microglial cells and reduced Aß phagocytosis. CONCLUSIONS: We provide evidence on the mechanism of action of A1AT on microglial-mediated neuroinflammation in vitro. Our in vitro data indicate that A1AT treatment modulates microglial cells in inflammatory conditions and that this modulation is due to an inhibition of calpain activity and intracellular calcium levels. The underlying mechanisms of the effects observed here are promising for future therapeutic strategies and should thus be further pursued in transgenic mouse models of Alzheimer disease.

Cerebral vasculitis as the clinical manifestation of neuroborreliosis: pattern of vascular pathology and prognostic factors of outcome.

BACKGROUND: Neuroborreliosis is a tick-borne condition that affects the central and/or peripheral nervous system. Cerebral infarction associated with neuroborreliosis-related vasculitis has been reported in only a handful of cases. Therefore, specific patterns of vascular pathology and prognostic outcome factors in these patients are still incompletely understood. AIMS: To determine the pattern of vascular pathology and prognostic outcome factors in patients with neuroborreliosis-related vasculitis. METHODS: We performed a longitudinal multicenter study between 1997 and 2022 in five academic study sites in Germany with a cumulative reference area of 1,620,000 inhabitants. All patients diagnosed with neuroborreliosis-associated cerebral vasculitis were included. The evaluation of clinical parameters, including NIH Stroke Scale (NIHSS), disability ranking (modified Rankin Scale, mRS), and neuroimaging with the estimation of patterns of vascular involvement were performed at admission as well as after three and twelve months. Linear regression analysis was used to identify the independent predictors of recurrent strokes, involvement of posterior circulation or multiple vessels. RESULTS: Patients with neuroborreliosis-related vasculitis (n=51) were relatively young (mean age: females: 60±11 years; male patients: 60±8 years) and displayed a predominance of vascular events within the posterior circulation (60.8%). A history of smoking was linked to recurrent strokes/TIA (64.7% vs. 23.5%; p=0.006), strokes in multiple territories (100% vs. 35.9%; p<0.0001), and posterior circulation events (64.5% vs. 30.0%, p=0.017), whereas other cardiovascular risk factors showed no significant differences. Linear regression analysis further confirmed smoking's significant association with recurrent strokes/ transient ischemic attacks (B: 0.412; p=0.002), multiple territory strokes/TIA (B: 0.467; p=0.033), and posterior circulation events (B: 0.317; p=0.033). CONCLUSION: A thorough CSF examination for neuroborreliosis is crucial, especially in younger stroke patients, particularly those experiencing posterior circulation ischemic events. Smoking-cessation should be prompted in patients with neuroborreliosis-associated cerebral vasculitis.

Mechanisms of action of naturally occurring antibodies against ß-amyloid on microglia.

BACKGROUND: Naturally occurring autoantibodies against amyloid-ß (nAbs-Aß) have been shown to exert beneficial effects on transgenic Alzheimer's disease (AD) animals in vivo and on primary neurons in vitro. Not much is known about their effect on microglial cells. Our aim was to investigate the effect of nAbs-Aß on amyloid-ß (Aß)-treated microglial cells in vitro with respect to cell viability, stress pathways, cytokine production and phagocytotic abilities and whether these effects can be conveyed to neurons. METHODS: Primary microglial cells isolated from Swiss Webster mouse mesencephalons on embryonic day 13.5 were pretreated with nAbs-Aß and then treated with Aß oligomers. After 3 hours, phagocytosis as well as western blot analysis were evaluated to measure the amount of phagocytized Aß. Cell viability was analyzed using an MTT assay 24 hours after treatment. Pro-inflammatory cytokines in the supernatants were analyzed with ELISAs and then we treated primary neuronal cells with these conditioned microglia supernatants. Twenty-four hours later we did a MTT assay of the treated neurons. We further investigated the effect of a single nAbs-Aß administration on Tg2576 mice in vivo. RESULTS: Upon co-administration of Aß and nAbs-Aß no change in microglia viability was observed. However, there was an increase in phosphorylated p38 protein level, an increase in the pro-inflammatory cytokines TNF-α and IL-6 and an increase in Aß uptake by microglial cells. Treatment of primary neurons with conditioned microglia medium led to a 10% improvement in cell viability when nAbs-Aß were co-administered compared to Aß-treated cells alone. We were unable to detect changes in cytokine production in brain lysates of Tg2576 mice. CONCLUSIONS: We provide evidence on the mechanism of action of nAbs-Aß on microglia in vitro. Interestingly, our in vivo data indicate that nAbs-Aß administration should be considered as a therapeutic strategy in AD, since there is no inflammatory reaction.

Naturally occurring autoantibodies against ß-Amyloid.

Naturally occurring antibodies (NAbs) have been described for more than 30 years. Recently, NAbs against ß-Amyloid and against other proteins involved in neurodegenerative disorders have been detected in humans. Based on the current evidence, it is hypothesized that anti-Aß NAbs can inhibit the fibrillation and toxicity of ß-aymloid, can improve cognition in a transgenic mouse model and interfere with oligomers of Aß. Different functions of these NAbs have been described in the current literature. Based on the results of the diverse studies a Phase-III study using IVIG has been initiated in patients with AD. The results will show whether the application of NAbs will change the fate of the disease. This chapter summarizes our current knowledge on NAbs against Aß.

Alpha-Synuclein-Specific Naturally Occurring Antibodies Inhibit Aggregation In Vitro and In Vivo.

Parkinson's disease (PD) is associated with motor and non-motor symptoms and characterized by aggregates of alpha-synuclein (αSyn). Naturally occurring antibodies (nAbs) are part of the innate immune system, produced without prior contact to their specific antigen, and polyreactive. The abundance of nAbs against αSyn is altered in patients with PD. In this work, we biophysically characterized nAbs against αSyn (nAbs-αSyn) and determined their biological effects. nAbs-αSyn were isolated from commercial intravenous immunoglobulins using column affinity purification. Biophysical properties were characterized using a battery of established in vitro assays. Biological effects were characterized in HEK293T cells transiently transfected with fluorescently tagged αSyn. Specific binding of nAbs-αSyn to monomeric αSyn was demonstrated by Dot blot, ELISA, and Surface Plasmon Resonance. nAbs-αSyn did not affect viability of HEK293T cells as reported by Cell Titer Blue and LDH Assays. nAbs-αSyn inhibited fibrillation of αSyn reported by the Thioflavin T aggregation assay. Altered fibril formation was confirmed with atomic force microscopy. In cells transfected with EGFP-tagged αSyn we observed reduced formation of aggresomes, perinuclear accumulations of αSyn aggregates. The results demonstrate that serum of healthy individuals contains nAbs that specifically bind αSyn and inhibit aggregation of αSyn in vitro. The addition of nAbs-αSyn to cultured cells affects intracellular αSyn aggregates. These findings help understanding the role of the innate immune systems for the pathogenesis of PD and suggest that systemic αSyn binding agents could potentially affect neuronal αSyn pathology.

Projected numbers of people with movement disorders in the years 2030 and 2050.

BACKGROUND: Movement disorders are chronic diseases with an increasing prevalence in old age. Because these disorders pose a major challenge to patients, families, and health care systems, there is a need for reliable data about the future number of affected people. PATIENTS AND METHODS: We searched the literature to identify epidemiological studies to obtain age-specific prevalence data of movement disorders. We combined the age-specific prevalence data with population projections for Europe, the United States, and Canada. RESULTS: Movement disorders will increase considerably between 2010 and 2050. The highest increase will be for dementia with Lewy bodies. In several countries, we project a near doubling of patients with PD. CONCLUSIONS: There will be a strong increase in the number of people affected by most movement disorders between 2010 and 2050. This increase will mostly depend on the future aging of populations in terms of their age structure and future life expectancy.

Health-related quality of life in patients with a history of myocardial infarction and stroke.

BACKGROUND: There is a lack of the generic data comparing the influence of different diseases on health-related quality of life (HrQoL) in a representative sample of primary care patients. METHODS: Patient data were collected in the DETECT (Diabetes Cardiovascular Risk Evaluation: Targets and Essential Data for Commitment of Treatment) study including 55,000 patients. RESULTS: 3,109 patients (33.3% female) with myocardial infarction (MI), stroke or both were compared to patients with a wide range of other diagnoses. Stroke and MI patients revealed a lower HrQoL as compared to patients with other diagnoses. Stroke was associated with strongest quality of life reduction. Multivariate analysis revealed several different determining factors. CONCLUSIONS: The reduction of HrQoL of patients with MI and stroke is primarily determined by the CNS insult. These data provide further evidence that early diagnosis and treatment of cardiovascular risk factors is essential to reduce subsequent stroke.

Bupropion for the Treatment of Apathy in Alzheimer Disease: A Randomized Clinical Trial.

Importance: Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients' and caregivers' quality of life. Effective treatment options are needed. Objective: To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type. Design, Setting, and Participants: This 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019. Interventions: Patients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study. Main Outcomes and Measures: Change on the Apathy Evaluation Scale-Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks. Results: A total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI, -0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change, -1.66; 95% CI, -3.01 to -0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change, -2.92; 95% CI, -5.89 to 0.06; P = .05) and cognition (mean change, -0.27; 95% CI, -3.26 to 2.73; P = .86). The numbers of adverse events (bupropion group, 39 patients [72.2%]; placebo group, 33 patients [61.1%]) and serious adverse events (bupropion group, 5 patients [9.3%]; placebo group, 2 patients [3.7%]) were comparable between groups. Conclusions and Relevance: Although it is safe, bupropion was not superior to placebo for the treatment of apathy in patients with dementia of Alzheimer type in the absence of clinically relevant depressed mood. Trial Registration: EU Clinical Trials Register Identifier: 2007-005352-17.

Role of MIF in inflammation and tumorigenesis.

MIF has been described as a protein that plays an essential role in both innate and acquired immunity. Previous studies have demonstrated that MIF activates lymphocytes, granulocytes and monocytes/macrophages. Furthermore, MIF can counteract the physiological function of steroids, thus playing a role in immune system regulation. Further evidence for a role of MIF in immunity was obtained in mouse models of autoimmune disorders, where the inhibition of MIF resulted in a more benign disease progression. This observation made MIF an attractive therapeutic target for the treatment of these disorders. Moreover, MIF expression was found to be upregulated in a variety of different tumor cells, a finding that further attracted interest. This review provides an overview of the involvement of MIF in both autoimmune disorders and tumorigenesis and summarizes the molecular action of MIF in this context.