Impaired Cognition in Narcolepsy: clinical and neurobiological perspectives.

In addition to well-known symptoms such as sleepiness and cataplexy, many people with narcolepsy have impaired cognition, reporting inattention, poor memory and other concerns. Unfortunately, research on cognition in narcolepsy has been limited. Strong evidence demonstrates difficulties with sustained attention, but evidence for executive dysfunction and impaired memory is mixed. Animal research provides some insights into how loss of the orexin neurons in narcolepsy type 1 may give rise to impaired cognition via dysfunction of the prefrontal cortex, and cholinergic and monoaminergic systems. This paper reviews some of these clinical and preclinical findings, provides a neurobiological framework to understand these deficits, and highlights some of the many key unanswered questions.

Author Correction: Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice.

In the version of this article initially published, the Simons Foundation was missing from the list of sources of support to P.T.T. in the Acknowledgments. The error has been corrected in the HTML and PDF versions of the article.

Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice.

Cerebellar abnormalities, particularly in Right Crus I (RCrusI), are consistently reported in autism spectrum disorders (ASD). Although RCrusI is functionally connected with ASD-implicated circuits, the contribution of RCrusI dysfunction to ASD remains unclear. Here neuromodulation of RCrusI in neurotypical humans resulted in altered functional connectivity with the inferior parietal lobule, and children with ASD showed atypical functional connectivity in this circuit. Atypical RCrusI-inferior parietal lobule structural connectivity was also evident in the Purkinje neuron (PN) TscI ASD mouse model. Additionally, chemogenetically mediated inhibition of RCrusI PN activity in mice was sufficient to generate ASD-related social, repetitive, and restricted behaviors, while stimulation of RCrusI PNs rescued social impairment in the PN TscI ASD mouse model. Together, these studies reveal important roles for RCrusI in ASD-related behaviors. Further, the rescue of social behaviors in an ASD mouse model suggests that investigation of the therapeutic potential of cerebellar neuromodulation in ASD may be warranted.

Update on monitoring and adverse effects of first generation disease modifying therapies and their recently approved versions in relapsing forms of multiple sclerosis.

PURPOSE OF REVIEW: As of April 2015, 13 disease modifying therapies (DMTs) have been approved by the Food and Drug Administration. The older agents continue to be utilized across the globe, especially in developing countries where many newer DMTs are still not available. Even though first generation DMTs have modest efficacy they have long term safety profile, and are considered safer than the second generation DMTs. RECENT FINDINGS: A PEGylated interferon beta-1a preparation that is administered subcutaneously every 2 weeks was also recently approved. Less frequent administration potentially reduced administration associated side effects and may improve adherence and compliance. The polyethylene glycol is also thought to make the drug less immunogenic. Glatopa (a glatiramer acetate bioequivalent), now represents the first available generic alternative of a DMT for multiple sclerosis. Its dosing, route of administration, and side effects are the same as for Copaxone. SUMMARY: In this article, we review the potential adverse effects and recommended laboratory studies as part of the monitoring strategy following initiation of various first generation DMTs and their recently approved versions.

Update on monitoring and adverse effects of approved second-generation disease-modifying therapies in relapsing forms of multiple sclerosis.

PURPOSE OF REVIEW: There has been a considerable increase in the number of disease-modifying therapies (DMTs) in recent years. It appears that the number of approved DMTs is going to continue to increase in the coming years. The growing number of DMTs has provided a challenge to the clinician to tailor their therapeutic recommendations based on patients' needs and preferences. To choose between these DMTs, knowledge of side-effect profiles is imperative. RECENT FINDINGS: Alemtuzumab, a humanized recombinant monoclonal antibody, was recently approved for the management of relapsing forms of multiple sclerosis. Its use seems to be limited by significant adverse effects and regular monitoring requirement. In 2014, the first case of progressive multifocal leukoencephalopathy (PML) was diagnosed in a patient with relapsing remitting multiple sclerosis who received extended dimethyl fumarate without any significant confounding factors. Among patients receiving fingolimod after previous natalizumab treatment, there have been 17 suspected cases of PML. There have also been three confirmed cases of PML in individuals who received fingolimod without previous natalizumab treatment. SUMMARY: In this review, we outline the potential adverse effects and recommended laboratory studies as part of the monitoring strategy following initiation of various DMTs.

Intractable and highly active relapsing multiple sclerosis - role of alemtuzumab.

Alemtuzumab is a humanized recombinant monoclonal antibody that was recently approved by the US Food and Drug Administration and the European Medicines Agency for the management of relapsing forms of multiple sclerosis (MS). It has been utilized for the management of chronic lymphocytic leukemia, bone marrow and renal transplantation, or graft versus host disease. Because of its immunomodulatory properties, it was brought into clinical development in MS. One Phase II (CAMMS223) and two Phase III clinical trials (CARE-MSI and -II) have evaluated the safety and efficacy of alemtuzumab in patients with relapsing-remitting MS. Even though its efficacy profile and long-lasting effect have attracted much interest among physicians and patients, it has significant potential adverse effects that may limit its use to patients with active disease. Here, we review the history of drug development of alemtuzumab. Furthermore, we outline the postulated mechanisms of action, clinical evidence, and safety of alemtuzumab for its use as a disease-modifying agent in active and highly active MS.

Mutant surfactant A2 proteins associated with familial pulmonary fibrosis and lung cancer induce TGF-ß1 secretion.

Mutations in the genes encoding the lung surfactant proteins are found in patients with interstitial lung disease and lung cancer, but their pathologic mechanism is poorly understood. Here we show that bronchoalveolar lavage fluid from humans heterozygous for a missense mutation in the gene encoding surfactant protein (SP)-A2 (SFTPA2) contains more TGF-ß1 than control samples. Expression of mutant SP-A2 in lung epithelial cells leads to secretion of latent TGF-ß1, which is capable of autocrine and paracrine signaling. TGF-ß1 secretion is not observed in lung epithelial cells expressing the common SP-A2 variants or other misfolded proteins capable of increasing cellular endoplasmic reticulum stress. Activation of the unfolded protein response is necessary for maximal TGF-ß1 secretion because gene silencing of the unfolded protein response transducers leads to an ∼50% decrease in mutant SP-A2-mediated TGF-ß1 secretion. Expression of the mutant SP-A2 proteins leads to the coordinated increase in gene expression of TGF-ß1 and two TGF-ß1-binding proteins, LTBP-1 and LTBP-4; expression of the latter is necessary for secretion of this cytokine. Inhibition of the TGF-ß autocrine positive feedback loop by a pan-TGF-ß-neutralizing antibody, a TGF-ß receptor antagonist, or LTBP gene silencing results in the reversal of TGF-ß-mediated epithelial-to-mesenchymal transition and cell death. Because secretion of latent TGF-ß1 is induced specifically by mutant SP-A2 proteins, therapeutics targeted to block this pathway may be especially beneficial for this molecularly defined subgroup of patients.

Lack of clinical AIDS in SIV-infected sooty mangabeys with significant CD4+ T cell loss is associated with double-negative T cells.

SIV infection of natural host species such as sooty mangabeys results in high viral replication without clinical signs of simian AIDS. Studying such infections is useful for identifying immunologic parameters that lead to AIDS in HIV-infected patients. Here we have demonstrated that acute, SIV-induced CD4(+) T cell depletion in sooty mangabeys does not result in immune dysfunction and progression to simian AIDS and that a population of CD3(+)CD4(-)CD8(-) T cells (double-negative T cells) partially compensates for CD4(+) T cell function in these animals. Passaging plasma from an SIV-infected sooty mangabey with very few CD4(+) T cells to SIV-negative animals resulted in rapid loss of CD4(+) T cells. Nonetheless, all sooty mangabeys generated SIV-specific antibody and T cell responses and maintained normal levels of plasma lipopolysaccharide. Moreover, all CD4-low sooty mangabeys elicited a de novo immune response following influenza vaccination. Such preserved immune responses as well as the low levels of immune activation observed in these animals were associated with the presence of double-negative T cells capable of producing Th1, Th2, and Th17 cytokines. These studies indicate that SIV-infected sooty mangabeys do not appear to rely entirely on CD4(+) T cells to maintain immunity and identify double-negative T cells as a potential subset of cells capable of performing CD4(+) T cell-like helper functions upon SIV-induced CD4(+) T cell depletion in this species.

Gamma/Delta T cell mRNA levels decrease at mucosal sites and increase at lymphoid sites following an oral SIV infection of macaques.

The oral and esophageal mucosa have been identified as possible sites of HIV/SIV entry following oral infection. Here, gamma/delta (gammadelta) T cells, a multi-functional T cell subset, were assessed at oral/esophageal mucosa and lymphoid sites at the earliest times (1-14 days) post-oral SIV inoculation utilizing quantitative RT-PCR. During these earliest times post-infection, decreased gammadelta TCR mRNA levels were observed at the oral gingiva and esophageal mucosa, while increased levels were observed within regional lymph nodes (cervical and retropharyngeal). Higher lymph node gammadelta TCR levels were associated with increased mRNA expression of the lymphoid homing chemokine/receptor (CCL21/CCR7) pair in these lymph nodes. In contrast to gammadelta TCR levels, CD4 mRNA expression remained relatively stable through 4 days post-infection, and depletion of CD4 T cells was only evident after 7 or 14 days post-infection. The decrease of gammadelta T cell mRNA from mucosal sites and the corresponding increase at lymphoid sites suggest a rapid redistribution of these immune cells at these earliest times post-SIV infection.