Amyloid-beta antibody binding to cerebral amyloid angiopathy fibrils and risk for amyloid-related imaging abnormalities.

Therapeutic antibodies have been developed to target amyloid-beta (Aß), and some of these slow the progression of Alzheimer's disease (AD). However, they can also cause adverse events known as amyloid-related imaging abnormalities with edema (ARIA-E). We investigated therapeutic Aß antibody binding to cerebral amyloid angiopathy (CAA) fibrils isolated from human leptomeningeal tissue to study whether this related to the ARIA-E frequencies previously reported by clinical trials. The binding of Aß antibodies to CAA Aß fibrils was evaluated in vitro using immunoprecipitation, surface plasmon resonance, and direct binding assay. Marked differences in Aß antibody binding to CAA fibrils were observed. Solanezumab and crenezumab showed negligible CAA fibril binding and these antibodies have no reported ARIA-E cases. Lecanemab showed a low binding to CAA fibrils, consistent with its relatively low ARIA-E frequency of 12.6%, while aducanumab, bapineuzumab, and gantenerumab all showed higher binding to CAA fibrils and substantially higher ARIA-E frequencies (25-35%). An ARIA-E frequency of 24% was reported for donanemab, and its binding to CAA fibrils correlated with the amount of pyroglutamate-modified Aß present. The findings of this study support the proposal that Aß antibody-CAA interactions may relate to the ARIA-E frequency observed in patients treated with Aß-based immunotherapies.

In vivo imaging of alpha-synuclein with antibody-based PET.

The protein alpha-synuclein (αSYN) plays a central role in synucleinopathies such as Parkinsons's disease (PD) and multiple system atrophy (MSA). Presently, there are no selective αSYN positron emission tomography (PET) radioligands that do not also show affinity to amyloid-beta (Aß). We have previously shown that radiolabeled antibodies, engineered to enter the brain via the transferrin receptor (TfR), is a promising approach for PET imaging of intrabrain targets. In this study, we used this strategy to visualize αSYN in the living mouse brain. Five bispecific antibodies, binding to both the murine TfR and αSYN were generated and radiolabeled with iodine-125 or iodine-124. All bispecific antibodies bound to αSYN and mTfR before and after radiolabelling in an ELISA assay, and bound to brain sections prepared from αSYN overexpressing mice as well as human PD- and MSA subjects, but not control tissues in autoradiography. Brain concentrations of the bispecific antibodies were between 26 and 63 times higher than the unmodified IgG format 2 h post-injection, corresponding to about 1.5% of the injected dose per gram brain tissue. Additionally, intrastriatal αSYN fibrils were visualized with PET in an αSYN deposition mouse model with one of the bispecific antibodies, [124I]RmAbSynO2-scFv8D3. However, PET images acquired in αSYN transgenic mice with verified brain pathology injected with [124I]RmAbSynO2-scFv8D3 and [124I]RmAb48-scFv8D3 showed no increase in antibody retention compared to WT mice. Despite successful imaging of deposited extracellular αSYN using a brain-penetrating antibody-based radioligand with no cross-specificity towards Aß, this proof-of-concept study demonstrates challenges in imaging intracellular αSYN inclusions present in synucleinopathies.

ABBV-0805, a novel antibody selective for soluble aggregated α-synuclein, prolongs lifespan and prevents buildup of α-synuclein pathology in mouse models of Parkinson's disease.

A growing body of evidence suggests that aggregated α-synuclein, the major constituent of Lewy bodies, plays a key role in the pathogenesis of Parkinson's disease and related α-synucleinopathies. Immunotherapies, both active and passive, against α-synuclein have been developed and are promising novel treatment strategies for such disorders. Here, we report on the humanization and pharmacological characteristics of ABBV-0805, a monoclonal antibody that exhibits a high selectivity for human aggregated α-synuclein and very low affinity for monomers. ABBV-0805 binds to a broad spectrum of soluble aggregated α-synuclein, including small and large aggregates of different conformations. Binding of ABBV-0805 to pathological α-synuclein was demonstrated in Lewy body-positive post mortem brains of Parkinson's disease patients. The functional potency of ABBV-0805 was demonstrated in several cellular assays, including Fcγ-receptor mediated uptake of soluble aggregated α-synuclein in microglia and inhibition of neurotoxicity in primary neurons. In vivo, the murine version of ABBV-0805 (mAb47) displayed significant dose-dependent decrease of α-synuclein aggregates in brain in several mouse models, both in prophylactic and therapeutic settings. In addition, mAb47 treatment of α-synuclein transgenic mice resulted in a significantly prolonged survival. ABBV-0805 selectively targets soluble toxic α-synuclein aggregates with a picomolar affinity and demonstrates excellent in vivo efficacy. Based on the strong preclinical findings described herein, ABBV-0805 has been progressed into clinical development as a potential disease-modifying treatment for Parkinson's disease.

Elevated soluble amyloid beta protofibrils in Down syndrome and Alzheimer's disease.

Down syndrome (DS) is caused by trisomy of chromosome 21, which leads to a propensity to develop amyloid ß (Aß) brain pathology in early adulthood followed later by cognitive and behavioral deterioration. Characterization of the Aß pathology is important to better understand the clinical deterioration of DS individuals and to identify interventive strategies. Brain samples from people with DS and Alzheimer's disease (AD), as well as non-demented controls (NDC), were analyzed with respect to different Aß species. Immunohistochemical staining using antibodies towards Aß was also performed. Elevated levels of soluble Aß protofibrils and insoluble Aßx-40 and Aßx-42 in formic acid brain extracts, and elevated immunohistochemical staining of Aß deposits were demonstrated with the antibody BAN2401 (lecanemab) in DS and AD compared with NDC. These data and the promising data in a large phase 2 CE clinical trial with lecanemab suggest that lecanemab may have the potential to preserve cognitive capacity in DS. Lecanemab is currently in a phase 3 CE clinical trial.

Open-label study with the monoamine stabilizer (-)-OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome.

OBJECTIVES: The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (-)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (-)-OSU6162 in ME/CFS was evaluated by means of observer-rated scales and self-assessment rating scales. MATERIALS AND METHODS: In the current study using an open-label single-arm design ME/CFS patient received treatment with (-)-OSU6162 during 12 weeks. The patients received the following doses of (-)-OSU6162: 15 mg b.i.d. during the first 4-week period, up to 30 mg b.i.d. during the second 4-week period and up to 45 mg b.i.d. during the third 4-week period, with follow-up visits after 16 and 20 weeks. RESULTS: Out of 33 included patients, 28 completed the 12 weeks treatment period. (-)-OSU6162 was well tolerated; only one patient discontinued due to an adverse event. Vital signs and physical examinations showed no abnormal changes. Blood analyses showed an increase in serum prolactin. Therapeutically, improvements were seen on the Clinical Global Impression of Change scale, the FibroFatigue scale, the Mental Fatigue Scale, the Fatigue Severity Scale, Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire. CONCLUSIONS: (-)-OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health-related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo-controlled double-blind trials.

Intramuscular vaccination with Strangvac is safe and induces protection against equine strangles caused by Streptococcus equi.

The equine disease strangles, caused by Streptococcus equi, remains a major cause of welfare and economic cost to the global horse industry. Here we report the safety, immunogenicity and efficacy of a novel multi-component chimeric fusion protein vaccine, called Strangvac, when administered to ponies via the intramuscular route. Across the four studies, Strangvac was safe and induced robust antibody responses towards the vaccine components in blood serum and the nasopharynx, which were boosted by revaccination up to 12 months after a primary course of 2 vaccinations 4 weeks apart. The vaccine response did not cross-react with a commercial strangles iELISA, which identifies horses that have been exposed to S. equi, demonstrating that it was possible to differentiate infected from vaccinated animals (DIVA). Following challenge with S. equi strain 4047 (Se4047), all 36 control ponies that had received an adjuvant-only placebo vaccine developed clinical signs of strangles. In contrast, intramuscular vaccination with Strangvac protected ponies significantly from challenge with Se4047 at two weeks (5 of 16 ponies protected (31%), P = 0.04) and two months (7 of 12 ponies protected (58%), P = 0.0046 (including pooled control data) after second vaccination. Optimal protection (15 of 16 ponies protected (94%), P < 0.0001) was observed following challenge at two weeks post-third vaccination. Our data demonstrate that Strangvac is safe, has DIVA capability and provides a rapid onset of protective immunity against strangles. We conclude that Strangvac is a valuable tool with which to protect horses from strangles, particularly during high-risk periods, whilst maintaining the mobility of horse populations as required by the global equine industry.

Intracerebroventricular delivery of vascular endothelial growth factor in patients with amyotrophic lateral sclerosis, a phase I study.

We studied the feasibility, safety, tolerability and pharmacokinetics of intracerebroventricular delivery of recombinant human vascular endothelial growth factor in patients with amyotrophic lateral sclerosis. In this phase I study in patients with amyotrophic lateral sclerosis, the study drug was delivered using an implantable programmable pump connected to a catheter inserted in the frontal horn of the lateral cerebral ventricle. A first cohort received open label vascular endothelial growth factor (0.2, 0.8 and 2 µg/day), a second cohort received placebo, 0.8 or 2 µg/day of study dug. After the 3-month study period, all patients could participate in an open label extension study. In total, 18 patients with amyotrophic lateral sclerosis, seen at the University Hospitals in Leuven were included. The surgical procedure was well tolerated in most patients. One patient had transient postoperative seizures, due to an ischemic lesion along the catheter tract. The first 3-month study period was completed by 15/18 patients. Administration of 2 µg/day vascular endothelial growth factor resulted in sustained detectable levels in cerebrospinal fluid. A pulmonary embolus occurred in 3 patients, in 1 patient in the first 3-month study, and in 2 patients during the open label extension study. The study drug was well tolerated in the other patients, for up to 6 years in the open label extension study. Our study shows that intracerebroventricular administration of 2 µg/day of vascular endothelial growth factor to patients with amyotrophic lateral sclerosis is feasible, results in detectable cerebrospinal fluid levels and is well tolerated in most patients. The most common serious adverse event was a pulmonary embolus.

Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients.

Myalgic encephalomyelitis, also referred to as chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by myalgia and a sometimes severe limitation of physical activity and cognition. It is exacerbated by physical and mental activity. Its cause is unknown, but frequently starts with an infection. The eliciting infection (commonly infectious mononucleosis or an upper respiratory infection) can be more or less well diagnosed. Among the human herpesviruses (HHV-1-8), HHV-4 (Epstein-Barr virus; EBV), HHV-6 (including HHV-6A and HHV-6B), and HHV-7, have been implicated in the pathogenesis of ME/CFS. It was therefore logical to search for serological evidence of past herpesvirus infection/reactivation in several cohorts of ME/CFS patients (all diagnosed using the Canada criteria). Control samples were from Swedish blood donors. We used whole purified virus, recombinant proteins, and synthetic peptides as antigens in a suspension multiplex immunoassay (SMIA) for immunoglobulin G (IgG). The study on herpesviral peptides based on antigenicity with human sera yielded novel epitope information. Overall, IgG anti-herpes-viral reactivities of ME/CFS patients and controls did not show significant differences. However, the high precision and internally controlled format allowed us to observe minor relative differences between antibody reactivities of some herpesviral antigens in ME/CFS versus controls. ME/CFS samples reacted somewhat differently from controls with whole virus HHV-1 antigens and recombinant EBV EBNA6 and EA antigens. We conclude that ME/CFS samples had similar levels of IgG reactivity as blood donor samples with HHV-1-7 antigens. The subtle serological differences should not be over-interpreted, but they may indicate that the immune system of some ME/CFS patients interact with the ubiquitous herpesviruses in a way different from that of healthy controls.

A randomised controlled trial of the monoaminergic stabiliser (-)-OSU6162 in treatment of myalgic encephalomyelitis/chronic fatigue syndrome.

OBJECTIVE: The monoaminergic stabiliser (-)-OSU6162 has in previous studies shown promising effects on mental fatigue after stroke and traumatic brain injury. This study investigated the safety and effectiveness of (-)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome. METHODS: A total of 62 patients were randomly assigned to placebo or (-)-OSU6162. Primary outcomes were assessment on the mental fatigue scale (MFS) and the clinical global impression of change (CGI-C) scale. Secondary outcomes were results on the FibroFatigue scale (FF), the Beck Depression Inventory (BDI), the pain visual analogue scale and neuropsychological tests. Assessments were performed at baseline, after 1 and 2 weeks of treatment and at follow-up after 6 weeks. RESULTS: MFS and CGI-C showed significant improvements for both treatment groups after treatment but not at follow-up; a similar pattern was seen for FF and BDI. However, significant differences between groups could not be demonstrated. On the other hand, correlation analyses showed a significant correlation between (-)-OSU6162 concentration and change in MFS, FF, and BDI score within the concentration interval 0.1-0.7 µM. Exploratory subgroup analyses showed a larger treatment effect with (-)-OSU6162 in improving MFS and FF symptoms in patients on antidepressant therapy compared to those without antidepressant treatment. CONCLUSION: (-)-OSU6162 was found to be safe and well tolerated. When analysing the entire material (-)-OSU6162 was not found to differ significantly from placebo in alleviating fatigue in ME patients but was superior to placebo in counteracting fatigue in a subgroup of ME patients who received concomitant pharmacological treatment for depression.

Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia.

BACKGROUND: Patients with myalgic encephalomyelitis (ME, also called chronic fatigue syndrome) may respond most favorably to frequent vitamin B12 injections, in vital combination with oral folic acid. However, there is no established algorithm for individualized optimal dosages, and rate of improvement may differ considerably between responders. OBJECTIVE: To evaluate clinical data from patients with ME, with or without fibromyalgia, who had been on B12 injections at least once a week for six months and up to several years. METHODS: 38 patients were included in a cross-sectional survey. Based on a validated observer's rating scale, they were divided into Good (n = 15) and Mild (n = 23) responders, and the two groups were compared from various clinical aspects. RESULTS: Good responders had used significantly more frequent injections (p<0.03) and higher doses of B12 (p<0.03) for a longer time (p<0.0005), higher daily amounts of oral folic acid (p<0.003) in good relation with the individual MTHFR genotype, more often thyroid hormones (p<0.02), and no strong analgesics at all, while 70% of Mild responders (p<0.0005) used analgesics such as opioids, duloxetine or pregabalin on a daily basis. In addition to ME, the higher number of patients with fibromyalgia among Mild responders was bordering on significance (p<0.09). Good responders rated themselves as "very much" or "much" improved, while Mild responders rated "much" or "minimally" improved. CONCLUSIONS: Dose-response relationship and long-lasting effects of B12/folic acid support a true positive response in the studied group of patients with ME/fibromyalgia. It's important to be alert on co-existing thyroid dysfunction, and we suspect a risk of counteracting interference between B12/folic acid and certain opioid analgesics and other drugs that have to be demethylated as part of their metabolism. These issues should be considered when controlled trials for ME and fibromyalgia are to be designed.

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients.

BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 µg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD. TRIAL REGISTRATION. Clinical Trials.gov NCT00866502. FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA).

Epitopes of microbial and human heat shock protein 60 and their recognition in myalgic encephalomyelitis.

Myalgic encephalomyelitis (ME, also called Chronic Fatigue Syndrome), a common disease with chronic fatigability, cognitive dysfunction and myalgia of unknown etiology, often starts with an infection. The chaperonin human heat shock protein 60 (HSP60) occurs in mitochondria and in bacteria, is highly conserved, antigenic and a major autoantigen. The anti-HSP60 humoral (IgG and IgM) immune response was studied in 69 ME patients and 76 blood donors (BD) (the Training set) with recombinant human and E coli HSP60, and 136 30-mer overlapping and targeted peptides from HSP60 of humans, Chlamydia, Mycoplasma and 26 other species in a multiplex suspension array. Peptides from HSP60 helix I had a chaperonin-like activity, but these and other HSP60 peptides also bound IgG and IgM with an ME preference, theoretically indicating a competition between HSP60 function and antibody binding. A HSP60-based panel of 25 antigens was selected. When evaluated with 61 other ME and 399 non-ME samples (331 BD, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients), a peptide from Chlamydia pneumoniae HSP60 detected IgM in 15 of 61 (24%) of ME, and in 1 of 399 non-ME at a high cutoff (p<0.0001). IgM to specific cross-reactive epitopes of human and microbial HSP60 occurs in a subset of ME, compatible with infection-induced autoimmunity.

No evidence for xenotropic murine leukemia-related virus infection in Sweden using internally controlled multiepitope suspension array serology.

Many syndromes have a large number of differential diagnoses, a situation which calls for multiplex diagnostic systems. Myalgic encephalomyelitis (ME), also named chronic fatigue syndrome (CFS), is a common disease of unknown etiology. A mouse retrovirus, xenotropic murine leukemia-related virus (XMRV), was found in ME/CFS patients and blood donors, but this was not corroborated. However, the paucity of serological investigations on XMRV in humans prompted us to develop a serological assay which cover many aspects of XMRV antigenicity. It is a novel suspension array method, using a multiplex IgG assay with nine recombinant proteins from the env and gag genes of XMRV and 38 peptides based on known epitopes of vertebrate gammaretroviruses. IgG antibodies were sought in 520 blood donors and 85 ME/CFS patients and in positive- and negative-control sera from animals. We found no differences in seroreactivity between blood donors and ME/CFS patients for any of the antigens. This did not support an association between ME/CFS and XMRV infection. The multiplex serological system had several advantages: (i) biotinylated protein G allowed us to run both human and animal sera, which is essential because of a lack of XMRV-positive humans; (ii) a novel quality control was a pan-peptide positive-control rabbit serum; and (iii) synthetic XMRV Gag peptides with degenerate positions covering most of the variation of murine leukemia-like viruses did not give higher background than nondegenerate analogs. The principle may be used for creation of variant tolerant peptide serologies. Thus, our system allows rational large-scale serological assays with built-in quality control.

Murine gammaretrovirus group G3 was not found in Swedish patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia.

BACKGROUND: The recent report of gammaretroviruses of probable murine origin in humans, called xenotropic murine retrovirus related virus (XMRV) and human murine leukemia virus related virus (HMRV), necessitated a bioinformatic search for this virus in genomes of the mouse and other vertebrates, and by PCR in humans. RESULTS: Three major groups of murine endogenous gammaretroviruses were identified. The third group encompassed both exogenous and endogenous Murine Leukemia Viruses (MLVs), and most XMRV/HMRV sequences reported from patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Two sensitive real-time PCRs for this group were developed. The predicted and observed amplification range for these and three published XMRV/HMRV PCRs demonstrated conspicuous differences between some of them, partly explainable by a recombinatorial origin of XMRV. Three reverse transcription real-time PCRs (RTQPCRs), directed against conserved and not overlapping stretches of env, gag and integrase (INT) sequences of XMRV/HMRV were used on human samples. White blood cells from 78 patients suffering from ME/CFS, of which 30 patients also fulfilled the diagnostic criteria for fibromyalgia (ME/CFS/FM) and in 7 patients with fibromyalgia (FM) only, all from the Gothenburg area of Sweden. As controls we analyzed 168 sera from Uppsala blood donors. We controlled for presence and amplifiability of nucleic acid and for mouse DNA contamination. To score as positive, a sample had to react with several of the XMRV/HMRV PCRs. None of the samples gave PCR reactions which fulfilled the positivity criteria. CONCLUSIONS: XMRV/HMRV like proviruses occur in the third murine gammaretrovirus group, characterized here. PCRs developed by us, and others, approximately cover this group, except for the INT RTQPCR, which is rather strictly XMRV specific. Using such PCRs, XMRV/HMRV could not be detected in PBMC and plasma samples from Swedish patients suffering from ME/CFS/FM, and in sera from Swedish blood donors.

Toxicokinetics of mercury after long-term repeated exposure to thimerosal-containing vaccine.

The preservative thimerosal contains ethyl mercury (EtHg). Concerns over possible toxicity have re-emerged recently due to its presence in (swine and other) flu vaccines. We examined the potential accumulation of mercury in adults given repeated injections of a thimerosal-preserved vaccine for many years. Fifteen female patients were recruited from an outpatient clinic running a clinical trial with repeated injections (1 ml every 3-4 weeks) of a staphylococcus toxoid vaccine containing 0.01% thimerosal to treat chronic fatigue syndrome. Fifteen untreated female patients with the same diagnoses served as controls. Blood samples were taken before injecting the vaccine, 1 day later, about 2 weeks later, and just before the next injection. In the 15 controls, samples were taken twice. Blood was analyzed for total mercury and EtHg. The toxicokinetics were assessed for each patient separately as well as with a population-based pharmacokinetic model. Total mercury in blood increased on Day 1 in all treated patients (median: 0.33, range: 0.17-1.3 µg/l), as did EtHg (median: 0.14 µg/l, range: 0.06-0.43 µg/l). After a few weeks, levels were back to normal and similar to those in controls. Levels of methyl mercury (MeHg; from fish consumption) were much higher than those of EtHg. After exclusion of an outlier, the mean half-life in a population-based model was 5.6 (95% CI: 4.8-6.3) days. The results indicate that mercury from thimerosal is not accumulated in blood in adults. This is in accordance with short half-lives and rapid metabolism of EtHg to inorganic mercury.

The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test.

We have earlier shown that the glucagon-like peptide 1 receptor agonist exendin-4 stimulates neurogenesis in the subventricular zone and excerts anti-parkinsonian behavior. The aim of this study was to assess the effects of exendin-4 treatment on hippocampus-associated cognitive and mood-related behavior in adult rodents. To investigate potential effects of exendin-4 on hippocampal function, radial maze and forced swim test were employed. The time necessary to solve a radial maze task and the duration of immobility in the forced swim test were significantly reduced compared to respective vehicle groups if the animals had received exendin-4 during 1-2weeks before testing. In contrast to the positive control imipramine, single administration of exendin-4 1h before the challenge in the forced swim test had no effect. Immunohistochemical analysis showed that the incorporation of bromodeoxyuridine, a marker for DNA synthesis, as well as doublecortin expression was increased in the hippocampal dentate gyrus following chronic treatment with exendin-4 compared to vehicle-treated controls. The neurogenic effect of exendin-4 on hippocampus was confirmed by quantitative PCR showing an upregulation of mRNA expression for Ki-67, doublecortin and Mash-1. Since exendin-4 significantly improves hippocampus-associated behavior in adult rodents, it may be a candidate for alleviation of mood and cognitive disorders.

Restorative effects of platelet derived growth factor-BB in rodent models of Parkinson's disease.

Parkinson's disease is characterized by motor deficits caused by loss of midbrain dopaminergic neurons. Neurotrophic factors and cell transplantation have partially restored function in models of Parkinson's disease, but have had limited effects in humans. Here we show that intracerebroventricular administration of platelet-derived growth factor-BB can offer an alternative strategy to restore function in Parkinson's disease; In animal models of nigrostriatal injury, a two weeks treatment with platelet-derived growth factor-BB resulted in long-lasting restoration of striatal dopamine transporter binding sites and expression of nigral tyrosine hydroxylase. It also normalized amphetamine-induced rotational behavior in 6-hydroxydopamine lesioned rats. Platelet-derived growth factor-BB promoted proliferation of neural progenitor cells in the subventricular zone. The effects on dopaminergic neurons and functional recovery could be blocked by co-infusion with a proliferation inhibitor, indicating a link between the proliferative and anti-parkinsonian effects. Based on the current data, we consider platelet-derived growth factor-BB a clinical candidate drug for treatment of Parkinson's disease.

A European multicenter randomized double-blind placebo-controlled monotherapy clinical trial of milnacipran in treatment of fibromyalgia.

OBJECTIVE: This randomized, double-blind, placebo-controlled, multicenter study investigated the efficacy and safety of milnacipran in the treatment of fibromyalgia (FM) in a European population. METHODS: Outpatients diagnosed with FM according to 1990 American College of Rheumatology criteria (N = 884) were randomized to placebo (n = 449) or milnacipran 200 mg/day (n = 435) for 17 weeks (4-week dose escalation, 12-week stable dose, 9-day down-titration), followed by a 2-week posttreatment period. The primary efficacy criterion was a 2-measure composite responder analysis requiring patients to achieve simultaneous improvements in pain (>or= 30% improvement from baseline in visual analog scale, 24-hour morning recall) and a rating of "very much" or "much" improved on the Patient Global Impression of Change scale. If responder analysis was positive, Fibromyalgia Impact Questionnaire (FIQ) was included as an additional key primary efficacy measure. RESULTS: At the end of the stable dose period (Week 16), milnacipran 200 mg/day showed significant improvements from baseline relative to placebo in the 2-measure composite responder criteria (p = 0.0003) and FIQ total score (p = 0.015). Significant improvements were also observed in multiple secondary efficacy endpoints, including Short-Form 36 Health Survey (SF-36) Physical Component Summary (p = 0.025), SF-36 Mental Component Summary (p = 0.007), Multidimensional Fatigue Inventory (p = 0.006), and Multiple Ability Self-Report Questionnaire (p = 0.041). Milnacipran was safe and well tolerated; nausea, hyperhidrosis, and headache were the most common adverse events. CONCLUSION: Milnacipran is an effective and safe treatment for pain and other predominant symptoms of FM. Registered as trial no. NCT00436033.

Association of MAOA gene functional promoter polymorphism with CSF dopamine turnover and atypical depression.

OBJECTIVE: Monoamine oxidase-A (MAO-A) is a key mitochondrial enzyme that metabolizes biogenic amine neurotransmitters such as dopamine and serotonin. Individuals with atypical depression (AD) are particularly responsive to treatment with MAO inhibitors (MAOIs). Biomarker tests are essential for prompt diagnosis of AD, and to identify those with an altered brain neurotransmitter metabolism who may selectively respond to MAOI therapy. METHODS: In a sample of 118 Scandinavian patients with treatment-resistant depression who are naive to MAOI therapy, we investigated the associations between a common MAOA functional promoter polymorphism (MAOA-uVNTR), cerebrospinal fluid (CSF) neurotransmitter metabolites, and AD susceptibility. The metabolites for dopamine (homovanillic acid, HVA), serotonin (5-hydroxyindoleacetic acid) and noradrenaline (3-methoxy-4-hydroxyphenylglycol) were measured in the CSF. RESULTS: AD was associated with the female sex and a higher HVA in CSF (P=0.008). The carriers of the MAOA-uVNTR short allele were significantly overrepresented among women with AD (P=0.005; odds ratio=4.76; 95% confidence interval=1.5-13.1; statistical power=80.0%). Moreover, the MAOA-uVNTR genotype significantly influenced the HVA concentration (P=0.01) and showed a strong trend in relation to 5-hydroxyindoleacetic acid concentration (P=0.057) in women. The mediational statistical analyses showed the CSF-HVA concentration as a key driver of the relationship between MAOA-uVNTR genotype and AD. CONCLUSION: The association of the MAOA-uVNTR with both susceptibility to AD and dopamine metabolite (HVA) concentration lends further biological plausibility for high MAO-A enzyme activity as a mechanistic factor for genetic predisposition to AD through altered dopamine turnover. Our observations provide new evidence on the in-vivo functional significance of the MAOA-uVNTR short allele as a high activity variant.