Effective Disease-modifying Treatment Research Articles

Risk factors for suicidal ideation in a chronic illness

Suicide is an urgent concern for people with chronic illnesses, particularly for those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Prior work has examined suicide risk in this illness, but few studies have examined specific risk factors. This study uses binary logistic regression to identify physical, social, and demographic risk and protective factors for suicidal ideation in ME/CFS (N = 559). The results indicate sleep-related symptoms, stigma, disability status, physical functioning, and marital status as risk factors for suicidal ideation in this group. These findings highlight the importance of education, de-stigmatization, and the search for effective disease-modifying treatments for ME/CFS.

Gene Transcription in End Stage Ankle Osteoarthritis Differs Markedly From Knee Arthritis and Non- Arthritic Ankles

Category: Ankle Arthritis; Arthroscopy; Basic Sciences/Biologics; Trauma Introduction/Purpose: Post-traumatic Osteoarthritis (OA) of the ankle is a debilitating condition that impacts millions of people. However, little is known about the genetic and epigenetic risk factors for progression to OA following injury. In order to better understand these factors, a thorough knowledge of the molecular signature in ankle OA relative to non-arthritic ankles is critical. The objective of this study was to perform RNA-sequencing of ankle joint synovial samples from OA and non-OA ankles to better characterize the synovial transcriptome. We compared synovial gene expression patterns in patients with end-stage OA with ankle synovium from non-OA ankles to investigate the unique biological pathways altered in ankle OA. Methods: Patients undergoing total ankle arthroplasty or ankle arthrodesis for end stage OA and patients undergoing ankle arthroscopic surgery for non-arthritic conditions (negative control), were consented for participation. Patients with immune disorders or inflammatory arthropathies were excluded. Patient demographics and medical history were collected. Synovial samples were harvested during surgery and RNA was isolated. Bulk 150 bp, paired-end RNA seq was performed using the Illumina NovaSeq6000 platform. Differential expression was determined using the edgeR (v3.16.5) package for R, after adjustment using a scaling normalization factor and P-values were corrected using the Benjamini Hochberg method. Similarities between samples were determined using Spearman Correlation and degree of similarity was visualized considering the first three Principal Components. Gene Ontology terms were identified to classify gene properties. Results: A total of 8 synovial samples from total ankle OA and 24 synovial samples from ankle non-OA were available for analysis. We found 808 genes uniquely expressed in OA synovium and another 786 different genes expressed in synovium from the control group. GO enrichment term analysis revealed an upregulation in endomembrane system organization, ubiquitin system/proteasomal degradation, and membrane transport processes including cytoskeletal, endosomal, and vacuolar in ankle OA samples compared to controls (Figure 1). These signatures differ from those previously identified in knee OA. Reactome analysis revealed pathways to those previously identified in OA of other joints, including TGF-beta signaling modulation. However, several signatures unique to ankle OA included extracellular matrix organization, integrin signaling, and AKT signaling modulation, among others. In addition, unlike in knee OA, reactome analyses of ankle OA synovium did not present with an inflammatory component associated with M1 macrophage infiltration. Conclusion: Ankle synovium in patients with end-stage ankle OA exhibit a transcriptomic signature distinct from ankle synovium collected from non-OA patients. More intriguing, we find that the ankle OA synovial transcriptome signature is distinct from previously published datasets studying synovium from patients with OA in other joints, particularly the knee. GO term and Reactome analyses identified signatures in bulk membrane transport, proteasome, matrix organization, integrin signaling, and AKT signaling, which are different from phenotypes previously reported in the knee. We conclude that development of effective disease modifying treatments for OA require attention to joint-specific biology and disease progression.

A Perspective: Challenges in Dementia Research.

Although dementia is a common and devastating disease that has been studied intensely for more than 100 years, no effective disease modifying treatment has been found. At this impasse, new approaches are important. The purpose of this paper is to provide, in the context of current research, one clinician’s perspective regarding important challenges in the field in the form of specific challenges. These challenges not only illustrate the scope of the problems inherent in finding treatments for dementia, but can also be specific targets to foster discussion, criticism and new research. One common theme is the need to transform research activities from small projects in individual laboratories/clinics to larger multinational projects, in which each clinician and researcher works as an integral part. This transformation will require collaboration between researchers, large corporations, regulatory/governmental authorities and the general population, as well as significant financial investments. However, the costs of transforming the approach are small in comparison with the cost of dementia.

Unmet Needs and Treatment of Relapsing-Remitting Multiple Sclerosis in Saudi Arabia: Focus on the Role of Ofatumumab.

Treatment-pattern data suggest that some patients with multiple sclerosis (MS) in the Kingdom of Saudi Arabia (KSA) may not be receiving optimal treatment. A virtual meeting of ten expert Saudi neurologists, held on October 23, 2020, discussed unmet needs in relapsing–remitting MS (RRMS), and the role of ofatumumab as a suitable treatment in the KSA. Multiple unmet needs were identified: poor quality of life, with high rates of depression and anxiety; a negative impact of MS on work ability; treatment choices that may compromise efficacy for safety or vice versa; inconvenient or complex dosage regimens; and limited access to patient education and support. Early use of highly effective disease-modifying treatments (DMTs) results in better patient outcomes than starting with less effective treatments and downstream escalation, but this strategy may be underutilized in the KSA. B cells are important in MS pathogenesis, and treatments targeting these may improve clinical outcomes. Ofatumumab differs from other B cell–depleting therapies, being a fully human monoclonal antibody that binds to CD20 at a completely separate site from the epitope bound by ocrelizumab, and being administered by subcutaneous injection. When compared with teriflunomide in two randomized, phase 3 clinical trials in patients with RRMS, ofatumumab was associated with significant reductions in annualized relapse rates, rates of confirmed disability worsening, and active lesions on magnetic resonance imaging. The incidence of adverse events, including serious infections, was similar with the two treatments. Ofatumumab is a valuable first- or second-line treatment option for RRMS in the KSA, particularly for patients who would benefit from highly effective DMTs early in the disease course, and for those who prefer the convenience of self-injection. Future research will clarify the position of ofatumumab in RRMS treatment, and comparative cost data may support the broad inclusion of ofatumumab in formularies across the KSA.

O-12: BUILDING LOCAL CAPACITY FOR HYDROXYUREA PHARMACOKINETICS AND PRECISION DOSING IN LOW-RESOURCE SETTINGS

Purpose: Hydroxyurea is a highly effective disease-modifying treatment for sickle cell anemia (SCA) and designated an Essential Medicine by the WHO. Increasing access to hydroxyurea for SCA in low-resource settings is advocated, but the ideal approach to dosing and monitoring is debated. Escalation to maximum tolerated dose (MTD) achieves superior benefits without additional toxicities but requires incremental dose adjustments with serial monitoring. Pharmacokinetic (PK)-guided dosing uses a test dose and sparse blood sampling to model hydroxyurea metabolism and predict a personalized optimal dose, which should require fewer clinical visits, lab assessments, and dose adjustments. Currently PK-guided dosing requires expensive, complex analyses that are unavailable in low-resource settings. A simplified method for hydroxyurea PK analysis, coupled with a user-friendly dosing algorithm, could simplify dosing and monitoring. Materials and methods: Concentrated stock solutions of reagents for chemical detection of serum hydroxyurea using high performance liquid chromatography (HPLC) were stored at -80C. On the day of analysis, hydroxyurea was serially diluted in human serum, then spiked with N-methylurea as an internal standard. After deproteination with trichloroacetic acid, a Fearon reaction to detect the urea moiety was performed with diacetylmonoxime, ferric chloride, sulfuric acid, and phosphoric acid. Thiosemicarbazide was added to minimize photolability of the colored product, which was analyzed using two commercial HPLC machines: (1) a standard benchtop Agilent HPLC system with a 449nm detector and 4.6mm x 250mm, 5 micron Zorbax Eclipse XDB-C18 column; and (2) a portable PolyLC SmartLife HPLC system with a 415nm detector and 4.6mm x 50mm, 3.5 micron Zorbax column XDB-C18 column (Figure 1). The mobile phases were acetonitrile and water. After validation in the US, the portable HPLC and chemicals were transported to Tanzania for repeat analyses. Results: A calibration curve was generated using the concentration of hydroxyurea dilutions ranging from 0mM to 1000mM, plotted against the hydroxyurea:N-methylurea ratio, and both HPLC systems yielded calibration curves with R2>0.99 (Figure 1). A separate stock of hydroxyurea was diluted to create known concentrations for analysis using the calibration curve, to confirm accuracy and precision within 10-20% of the known value. Both HPLC systems measured hydroxyurea concentrations with <10% variance from the prepared concentration. Paired analysis of samples on both machines yielded results with <15% variance. Serial measurements of a standard 100 mM concentration using the PolyLC system were precise with a 2.5% coefficient of variance. After transport to Tanzania, setup, and training, the SmartLife HPLC system was able to produce similar excellent hydroxyurea concentration calibration curves with R2>0.99. Conclusion: Improving access to hydroxyurea as an essential treatment for all children living with SCA requires an approach that eases financial and logistical barriers while optimizing safety and benefit, especially in low-resource settings. We modified a portable HPLC instrument to detect hydroxyurea, validated its precision and accuracy, and confirmed capacity building and knowledge transfer to a low-resource setting. Implementation of HPLC for measurement of serum hydroxyurea concentrations is now feasible in low resource settings using available laboratory infrastructure. PK-dosing of hydroxyurea may soon be possible, with initial treatment using a personalized optimal dose.Agilent (unmodified) and SmartLife (modified) HPLC instruments for measuring serum hydroxyurea concentrationsCalibration curve of 0-1000 µM hydroxyurea measured with SmartLife PolyLC high performance liquid chromatography system demonstrating excellent R2 value in both the US (A) and Tanzania (B). The authors do not declare any conflict of interest

Faecal microbiota transplant ameliorates gut dysbiosis and cognitive deficits in Huntington's disease mice.

Huntington’s disease is a neurodegenerative disorder involving psychiatric, cognitive and motor symptoms. Huntington’s disease is caused by a tandem-repeat expansion in the huntingtin gene, which is widely expressed throughout the brain and body, including the gastrointestinal system. There are currently no effective disease-modifying treatments available for this fatal disorder. Despite recent evidence of gut microbiome disruption in preclinical and clinical Huntington’s disease, its potential as a target for therapeutic interventions has not been explored. The microbiota–gut–brain axis provides a potential pathway through which changes in the gut could modulate brain function, including cognition. We now show that faecal microbiota transplant (FMT) from wild-type into Huntington’s disease mice positively modulates cognitive outcomes, particularly in females. In Huntington’s disease male mice, we revealed an inefficiency of FMT engraftment, which is potentially due to the more pronounced changes in the structure, composition and instability of the gut microbial community, and the imbalance in acetate and gut immune profiles found in these mice. This study demonstrates a role for gut microbiome modulation in ameliorating cognitive deficits modelling dementia in Huntington’s disease. Our findings pave the way for the development of future therapeutic approaches, including FMT and other forms of gut microbiome modulation, as potential clinical interventions for Huntington’s disease.

The role of mitochondrial dysfunction in Alzheimer's disease: A potential pathway to treatment.

Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is characterized by progressive memory loss and cognitive impairment. Our understanding of AD pathogenesis is limited and no effective disease-modifying treatment is available. Mitochondria are cytoplasmic organelles critical to the homeostatic regulation of glucose and energy in the cell. Mitochondrial abnormalities are found early in the course of AD and dysfunctional mitochondria are involved in AD progression. The resulting respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species are highly damaging to neurons. Restoration of mitochondrial function may provide a novel therapeutic strategy for AD. This review discusses the specifics of mitochondrial fragmentation, imbalances in fission and fusion, and DNA damage seen in AD and the contribution of compromised mitochondrial activity to AD etiopathogenesis. It explores how an understanding of the processes underlying mitochondrial failure may lead to urgently needed treatment innovations. It considers individual mitochondrial proteins that have emerged as promising drug targets and evaluates neuroprotective agents that could improve the functional state of mitochondria in the setting of AD. There is great promise in exploring original approaches to preserving mitochondrial viability as a means to achieve breakthroughs in treating AD.

CRISPR-Cas9-Based Technology and Its Relevance to Gene Editing in Parkinson's Disease.

Parkinson’s disease (PD) and other chronic and debilitating neurodegenerative diseases (NDs) impose a substantial medical, emotional, and financial burden on individuals and society. The origin of PD is unknown due to a complex combination of hereditary and environmental risk factors. However, over the last several decades, a significant amount of available data from clinical and experimental studies has implicated neuroinflammation, oxidative stress, dysregulated protein degradation, and mitochondrial dysfunction as the primary causes of PD neurodegeneration. The new gene-editing techniques hold great promise for research and therapy of NDs, such as PD, for which there are currently no effective disease-modifying treatments. As a result, gene therapy may offer new treatment options, transforming our ability to treat this disease. We present a detailed overview of novel gene-editing delivery vehicles, which is essential for their successful implementation in both cutting-edge research and prospective therapeutics. Moreover, we review the most recent advancements in CRISPR-based applications and gene therapies for a better understanding of treating PD. We explore the benefits and drawbacks of using them for a range of gene-editing applications in the brain, emphasizing some fascinating possibilities.

Communication Bridge™-2 (CB2): an NIH Stage 2 randomized control trial of a speech-language intervention for communication impairments in individuals with mild to moderate primary progressive aphasia

BackgroundPrimary progressive aphasia (PPA) is a clinical dementia syndrome. Impairments in language (speaking, reading, writing, and understanding) are the primary and persistent symptoms. These impairments progress insidiously and devastate communication confidence, participation, and quality of life for persons living with PPA. Currently, there are no effective disease modifying treatments for PPA. Speech-language interventions hold promise for mitigating communication challenges and language symptoms. However, evidence regarding their efficacy in PPA is of low quality and there are currently no rigorous randomized trials.MethodCommunication Bridge™-2 (CB2) is a Stage 2, superiority, single-blind, randomized, parallel group, active-control, behavioral clinical trial delivered virtually within a telehealth service delivery model to individuals with PPA. Ninety carefully characterized participants with clinically confirmed PPA will be randomized to one of two speech-language intervention arms: (1) Communication Bridge™ a dyadic intervention based in communication participation therapy models that incorporates salient training stimuli or (2) the control intervention a non-dyadic intervention based in impairment therapy models addressing word retrieval and language production that incorporates fixed stimuli. The superiority of Communication Bridge™ over the Control arm will be evaluated using primary outcomes of communication confidence and participation. Other outcomes include accuracy for trained words and scripts. Participants complete two therapy blocks over a 12-month period. Outcomes will be measured at baseline, at each therapy block, and at 12 months post enrollment.DiscussionThe CB2 trial will supply Level 2 evidence regarding the efficacy of the Communication Bridge™ intervention delivered in a telehealth service delivery model for individuals with mild to moderate PPA. An important by-product of the CB2 trial is that these data can be used to evaluate the efficacy of speech-language interventions delivered in both trial arms for persons with PPA. The impact of these data should not be overlooked as they will yield important insights examining why interventions work and for whom, which will advance effectiveness trials for speech-language interventions in PPA.Trial RegistrationClinicalTrials.govNCT03371706. Registered prospectively on December 13, 2017.

Recent Advances in Microglia Modelling to Address Translational Outcomes in Neurodegenerative Diseases.

Neurodegenerative diseases are deteriorating conditions of the nervous system that are rapidly increasing in the ageing population. Increasing evidence suggests that neuroinflammation, largely mediated by microglia, the resident immune cells of the brain, contributes to the onset and progression of neurodegenerative diseases. Hence, microglia are considered a major therapeutic target that could potentially yield effective disease-modifying treatments for neurodegenerative diseases. Despite the interest in studying microglia as drug targets, the availability of cost-effective, flexible, and patient-specific microglia cellular models is limited. Importantly, the current model systems do not accurately recapitulate important pathological features or disease processes, leading to the failure of many therapeutic drugs. Here, we review the key roles of microglia in neurodegenerative diseases and provide an update on the current microglial plaforms utilised in neurodegenerative diseases, with a focus on human microglia-like cells derived from peripheral blood mononuclear cells as well as human-induced pluripotent stem cells. The described microglial platforms can serve as tools for investigating disease biomarkers and improving the clinical translatability of the drug development process in neurodegenerative diseases.

Evidence of protective effects of recombinant ADAMTS13 in a humanized model of sickle cell disease.

Sickle cell disease (SCD) is an inherited red blood cell disorder that occurs worldwide. Acute vaso-occlusive crisis is the main cause of hospitalization in patients with SCD. There is growing evidence that inflammatory vasculopathy plays a key role in both acute and chronic SCD-related clinical manifestations. In a humanized mouse model of SCD, we found an increase of von Willebrand factor activity and a reduction in the ratio of a disintegrin and metalloproteinase with thrombospondin type 1 motif, number 13 (ADAMTS13) to von Willebrand factor activity similar to that observed in the human counterpart. Recombinant ADAMTS13 was administered to humanized SCD mice before they were subjected to hypoxia/reoxygenation (H/R) stress as a model of vaso-occlusive crisis. In SCD mice, recombinant ADAMTS13 reduced H/R-induced hemolysis and systemic and local inflammation in lungs and kidneys. It also diminished H/R-induced worsening of inflammatory vasculopathy, reducing local nitric oxidase synthase expression. Collectively, our data provide for the firsttime evidence that pharmacological treatment with recombinant ADAMTS13 (TAK-755) diminished H/R-induced sickle cell-related organ damage. Thus, recombinant ADAMTS13 might be considered as a potential effective disease-modifying treatment option for sickle cell-related acute events.

Alemtuzumab induced hemodynamic change in relapsing multiple sclerosis occurs independent of corticosteroid premedication – a retrospective multicentre study

Background Alemtuzumab (ATZ), a highly effective disease modifying treatment for relapsing multiple sclerosis (MS), is associated with the rare risk of intracerebral hemorrhage. Increase of blood pressure (BP) was hypothesized to be causative, but prior administration of high-dose methylprednisolone (HDMP) is a potential confounder.Objective To analyze BP change in MS patients treated with ATZ and prior HDMP treatment compared to patients receiving HDMP only for acute relapse.Methods In this retrospective study, 30 patients treated with ATZ/HDMP and 60 age-, sex- and disability-matched controls treated with HDMP were included. Primary endpoint was the change of systolic BP (SBP) between before ATZ cycle and the maximum value measured during the treatment cycle; secondary endpoints were change in diastolic BP (DBP) and heart rate (HR).Results Change of SBP observed in ATZ/HDMP treated patients was significantly higher than in HDMP controls (mean maximal change of 12.8 vs. 8.1 mmHg, p = 0.033). An increase of SBP exceeding 20% from baseline was observed in 5 (16.7%) patients on ATZ/HDMP compared to 3 (5.0%) on HDMP (p = 0.078). The day after the 1st ATZ infusion, mean HR was higher in the ATZ/HDMP group compared to HDMP controls (82.5 vs. 73.2 bpm, p = 0.005), although there was no significant group difference over time.Conclusions ATZ treatment induced a slight, but significant increase in SBP independent of HDMP. Although hemodynamic alterations alone seem unlikely as putative mechanism for cerebral bleedings, strict cardiovascular monitoring is recommended to reduce rare, but severe cardiovascular side effects.

INVESTIGATING THE MECHANO-IMMUNE RESPONSE OF CARTILAGE AND THE SYNOVIAL MEMBRANE USING A JOINT-ON-CHIP APPROACH

Purpose: Arthritis, a joint disease affecting 10 percent of the population, is associated with synovial inflammation and/or improper mechanical stimulation. No effective disease-modifying treatment is available, which is partly due to the lack of reliable disease models. To address this, we have engineered and combined cartilage and synovial membrane on-chip models.

SEMI-QUANTITATIVE AND QUANTITATIVE CARTILAGE IMPROVEMENT AFTER INTRA-ARTICULAR INJECTION OF ICM-203 IN CANINE OA MODEL

Purpose: While inflammation in osteoarthritis (OA) needs to be controlled to attenuate OA pathogenesis, maintenance of proper dynamics of chondrocyte physiology would also be critical to inhibit the onset and early progression of OA. Due to the complicated etiology of OA, there are no effective disease-modifying treatments to date, and significant unmet medical needs exist for a disease-modifying OA drug (DMOAD). Nkx3.2 was initially identified as a pro-chondrogenic factor promoting cartilage development.

Decreased Intrathecal Concentrations of Free Light Chains Kappa in Multiple Sclerosis Patients Taking Very High Effective Disease-Modifying Treatment.

Free light chains kappa (FLCκ) in cerebrospinal fluid (CSF) are a part of the intrathecal immune response. This observational study was conducted to investigate the effects of different disease-modifying therapies (DMT) on the humoral intrathecal immune response in the CSF of patients with multiple sclerosis (MS). FLCκ were analyzed in CSF and serum samples from MS patients taking DMT (n = 60) and those in a control cohort of treatment-naïve MS patients (n = 90). DMT was classified as moderately effective (including INFß-1a, INFß-1b, glatiramer acetate, dimethyl fumarate, teriflunomide, triamcinolone); highly effective (including fingolimod, daclizumab) and very highly effective (alemtuzumab, natalizumab, rituximab/ocrelizumab, mitoxantrone). FLCκ were measured using a nephelometric FLCκ kit. Intrathecal FLCκ and IgG concentrations were assessed in relation to the hyperbolic reference range in quotient diagrams. Intrathecal FLCκ concentrations and IgG concentrations were significantly lower in samples from the cohort of MS patients taking very highly effective DMT than in samples from the cohort of MS patients taking highly effective DMT and in the treatment-naïve cohort (FLCκ: p = 0.004, p < 0.0001 respectively/IgG: p = 0.013; p = 0.021). The reduction in FLCκ could contribute to an anti-inflammatory effect in the CNS through this mechanism. There was no difference in the appearance of CSF-specific oligoclonal bands (p = 0.830). Longitudinal analyses are required to confirm these results.

Skin involvement in early diffuse cutaneous systemic sclerosis: an unmet clinical need.

Diffuse cutaneous systemic sclerosis (dcSSc) is associated with high mortality resulting from early internal-organ involvement. Clinicians therefore tend to focus on early diagnosis and treatment of potentially life-threatening cardiorespiratory and renal disease. However, the rapidly progressive painful, itchy skin tightening that characterizes dcSSc is the symptom that has the greatest effect on patients’ quality of life, and there is currently no effective disease-modifying treatment for it. Considerable advances have been made in predicting the extent and rate of skin-disease progression (which vary between patients), including the development of techniques such as molecular analysis of skin biopsy samples. Risk stratification for progressive skin disease is especially relevant now that haematopoietic stem-cell transplantation is a treatment option, because stratification will inform the balance of risk versus benefit for each patient. Measurement of skin disease is a major challenge. Results from clinical trials have highlighted limitations of the modified Rodnan skin score (the current gold standard). Alternative patient-reported and other potential outcome measures have been and are being developed. Patients with early dcSSc should be referred to specialist centres to ensure best-practice management, including the management of their skin disease, and to maximize opportunities for inclusion in clinical trials.

Recent Advances of Microneedles and Their Application in Disease Treatment.

For decades, scientists have been doing a lot of research and exploration to find effective long-term analgesic and/or disease-modifying treatments. Microneedles (MNs) are a simple, effective, and painless transdermal drug delivery technology that has emerged in recent years, and exhibits great promise for realizing intelligent drug delivery. With the development of materials science and fabrication technology, the MN transdermal drug delivery technology has been applied and popularized in more and more fields, including chronic illnesses such as arthritis or diabetes, cancer, dermatocosmetology, family planning, and epidemic disease prevention, and has made fruitful achievements. This paper mainly reviews the latest research status of MNs and their fabrication methodology, and summarizes the application of MNs in the treatment of various diseases, as well as the potential to use nanotechnology to develop more intelligent MNs-based drug delivery systems.

Communication Difficulties and their Association with Caregiving Burdens in Aphasic Dementia

Primary progressive aphasia (PPA) is a clinical dementia syndrome for which there is no effective disease-modifying treatment. Impairments in language are the primary and persistent symptoms, and severely limit participation in everyday activities and family conversations. Despite this, there are no published studies examining the objective relationship between conversation difficulties and caregiving burden in PPA. We tested the hypothesis that the severity of care partner perceived conversation difficulties predicts caregiving burden using the Perception of Conversation Difficulty-Dementia Alzheimer’s Type and the Montgomery Borgatta Caregiving Burden Scale. The analysis included baseline data from 78 care partners (62% female) enrolled in the Communication BridgeTM-2 randomized control clinical trial of a speech-language intervention for PPA. Care partners had a mean age of 64.5 years (SD=10.76) and a mean relationship duration with the PPA participant of 38.6 years (SD=15.29). Eighty-six percent were spouses, 5% were adult children, and the remaining 9% were friends or siblings. Higher ratings of conversation difficulties were associated with increased caregiving burden for both objective burden (p < 0.001) and subjective stress burden (p < 0.001). The relationship between conversation difficulties and objective burden was mediated by dependence in activities of daily living and care partner depression, whereas the relationship with subjective stress burden was mediated by depression only. This is the first large scale study of care partner reported conversation difficulties and caregiving burden in PPA. The finding that conversation difficulties have a direct relationship with caregiving burden is an important consideration for interventions and outcome measurement in PPA.

Metformin and fluoxetine improve depressive-like behavior in a murine model of Parkinsońs disease through the modulation of neuroinflammation, neurogenesis and neuroplasticity

Thereabout 30–40% of patients with Parkinson's Disease (PD) also have depression contributing to the loss of quality of life. Among the patients who treat depression, about 50% do not show significant improvement due to the limited efficacy of the treatment. So far, there are no effective disease-modifying treatments that can impede its progression. The current clinical approach is based on symptom management. Nonetheless, the reuse of drugs with excellent safety profiles represents an attractive alternative strategy for treating of different clinical aspects of PD. In this study, we evaluated the effects of metformin separately and associated with fluoxetine on depressive like-behavior and motor alterations in experimental Parkinson's disease. C57BL6 mice were induced with rotenone (2.5 mg/kg/day) for 20 days and treated with metformin (200 mg/kg/day) and fluoxetine (10 mg/kg/day) from the 5th day of induction. The animals were submitted to Sucrose Preference, Tail Suspension, and rotarod tests. Hippocampus, prefrontal cortex, and substantia nigra were dissected for molecular and morphological analysis. Metformin and fluoxetine prevented depressive-like behavior and improved motor impairment and increased TH nigral positive cells. Metformin and fluoxetine also reduced IBA-1 and GFAP positive cells in the hippocampus. Moreover, metformin reduced the phospho-NF-kB, IL-1β in the prefrontal cortex and iNOS levels in the hippocampus. Both metformin and fluoxetine increased neurogenesis by increasing KI67, but only the combined treatment increased neuronal survival by NeuN positive cells in the hippocampus. In addition, fluoxetine reduced cell death, decreasing caspase-3 and PARP-1 levels. Lastly, metformin potentiated the effect of fluoxetine on neuroplasticity by increasing BDNF positive cells. Metformin has antidepressant and antiparkinsonian potential due to anti-inflammatory neurogenic, and neuroplasticity-inducing effects when combined with fluoxetine.

Opportunities and Obstacles Associated With Sequential Immune Reconstitution Therapy for Multiple Sclerosis: A Case Report

Cladribine is an effective disease-modifying treatment for relapsing-remitting multiple sclerosis that acts as an immune reconstitution therapy and is administered in a pulsed manner. Despite its efficacy, severe disease reactivation early after treatment represents a serious clinical problem, and clear evidence to guide the management of such a situation is lacking. Here, we describe the case of a patient experiencing considerable disease activity during the 1st year after the initiation of cladribine treatment. The patient was switched to alemtuzumab and, therefore, received double immune reconstitution therapy. Data regarding this approach are lacking, and real-world observations may be of interest. Despite achieving good control of disease activity, we observed several serious infectious complications. Our results suggest that sequential immune reconstitution therapies may be effective; however, at the price of higher susceptibility to infections.