Cognitive Rehabilitation for Attention and Memory in people with Multiple Sclerosis: study protocol for a randomised controlled trial (CRAMMS).

BACKGROUND: People with multiple sclerosis have problems with memory and attention. Cognitive rehabilitation is a structured set of therapeutic activities designed to retrain an individual's memory and other cognitive functions. Cognitive rehabilitation may be provided to teach people strategies to cope with these problems, in order to reduce the impact on everyday life. The effectiveness of cognitive rehabilitation for people with multiple sclerosis has not been established. METHODS: This is a multi-centre, randomised controlled trial investigating the clinical and cost-effectiveness of a group-based cognitive rehabilitation programme for attention and memory problems for people with multiple sclerosis. Four hundred people with multiple sclerosis will be randomised from at least four centres. Participants will be eligible if they have memory problems, are 18 to 69 years of age, are able to travel to attend group sessions and give informed consent. Participants will be randomised in a ratio of 6:5 to the group rehabilitation intervention plus usual care or usual care alone. Intervention groups will receive 10 weekly sessions of a manualised cognitive rehabilitation programme. The intervention will include both restitution strategies to retrain impaired attention and memory functions and compensation strategies to enable participants to cope with their cognitive problems. All participants will receive a follow-up questionnaire and an assessment by a research assistant at 6 and 12 months after randomisation. The primary outcome is the Multiple Sclerosis Impact Scale (MSIS) Psychological subscale at 12 months. Secondary outcomes include the Everyday Memory Questionnaire, General Health Questionnaire-30, EQ-5D and a service use questionnaire from participants, and the Everyday Memory Questionnaire-relative version and Carer Strain Index from a relative or friend. The primary analysis will be based on intention to treat. A mixed-model regression analysis of the MSIS Psychological subscale at 12 months will be used to estimate the effect of the group cognitive rehabilitation programme. DISCUSSION: The study will provide evidence regarding the clinical and cost-effectiveness of a group-based cognitive rehabilitation programme for attention and memory problems in people with multiple sclerosis. TRIAL REGISTRATION: ISRCTN09697576 . Registered 14 August 2014.

Two quantitative trait loci affecting progressive hearing loss in 101/H mice.

Although recent progress in identifying genes involved in deafness has been remarkable, the genetic basis of progressive hearing loss (or age-related hearing loss) is poorly understood because of the extreme difficulty in studying such a late-onset, complex disease in human populations. Several inbred strains of mice such as 129P1/ReJ, C57BL/6J, DBA/2J, and BALB/cByJ have been reported to exhibit age-related hearing loss and provide valuable models for human nonsyndromic progressive deafness. In this article we show that 101/H mice also exhibit progressive deafness with early onset. Linkage analysis of F(2) populations derived from crosses between the 101/H and the MAI/Pas and MBT/Pas wild-derived mice suggested at least two major quantitative trait loci (QTLs) that influence progressive hearing loss. A first QTL, designated Phl1, was mapped with a maximum LOD score of 6.7 to the centromeric region of Chromosome 17, where no deafness-related QTL has been mapped so far. A second QTL, designated Phl2, mapped to Chromosome 10 and exhibited a maximum LOD score of 5.3. The map position of Phl2 near the well-known QTL of age-related hearing loss (Ahl) suggested the possibility of allelism, although the Ahl mutation itself did not segregate in these crosses. Finally, we found some evidence of epistatic interaction between Phl1 and Phl2.

Tmc1 is necessary for normal functional maturation and survival of inner and outer hair cells in the mouse cochlea.

The deafness (dn) and Beethoven (Bth) mutant mice are models for profound congenital deafness (DFNB7/B11) and progressive hearing loss (DFNA36), respectively, caused by recessive and dominant mutations of transmembrane cochlear-expressed gene 1 (TMC1), which encodes a transmembrane protein of unknown function. In the mouse cochlea Tmc1 is expressed in both outer (OHCs) and inner (IHCs) hair cells from early stages of development. Immature hair cells of mutant mice seem normal in appearance and biophysical properties. From around P8 for OHCs and P12 for IHCs, mutants fail to acquire (dn/dn) or show reduced expression (Bth/Bth and, to a lesser extent Bth/+) of the K+ currents which contribute to their normal functional maturation (the BK-type current IK,f in IHCs, and the delayed rectifier IK,n in both cell types). Moreover, the exocytotic machinery in mutant IHCs does not develop normally as judged by the persistence of immature features of the Ca2+ current and exocytosis into adulthood. Mutant mice exhibited progressive hair cell damage and loss. The compound action potential (CAP) thresholds of Bth/+ mice were raised and correlated with the degree of hair cell loss. Homozygous mutants (dn/dn and Bth/Bth) never showed CAP responses, even at ages where many hair cells were still present in the apex of the cochlea, suggesting their hair cells never function normally. We propose that Tmc1 is involved in trafficking of molecules to the plasma membrane or serves as an intracellular regulatory signal for differentiation of immature hair cells into fully functional auditory receptors.

Towards a mutant map of the mouse--new models of neurological, behavioural, deafness, bone, renal and blood disorders.

With the completion of the first draft of the human genome sequence, the next major challenge is assigning function to genes. One approach is genome-wide random chemical mutagenesis, followed by screening for mutant phenotypes of interest and subsequent mapping and identification of the mutated genes in question. We (a consortium made up of GlaxoSmithKline, the MRC Mammalian Genetics Unit and Mouse Genome Centre, Harwell, Imperial College, London, and the Royal London Hospital) have used ENU mutagenesis in the mouse for the rapid generation of novel mutant phenotypes for use as animal models of human disease and for gene function assignment (Nolan et al., 2000). As of 2003, 35,000 mice have been produced to date in a genome-wide screen for dominant mutations and screened using a variety of screening protocols. Nearly 200 mutants have been confirmed as heritable and added to the mouse mutant catalogue and, overall, we can extrapolate that we have recovered over 700 mutants from the screening programme. For further information on the project and details of the data, see http://www.mgu.har.mrc.ac.uk/mutabase.

An ENU-induced mutation in AP-2alpha leads to middle ear and ocular defects in Doarad mice.

One of the advantages of N-ethyl- N-nitrosourea (ENU)-induced mutagenesis is that, after randomly causing point mutations, a variety of alleles can be generated in genes leading to diverse phenotypes. For example, transcription factor AP-2alpha ( Tcfap2a) null homozygote mice show a large spectrum of developmental defects, among them missing middle ear bones and tympanic ring. This is the usual occurrence, where mutations causing middle ear anomalies usually coincide with other abnormalities. Using ENU-induced mutagenesis, we discovered a new dominant Tcfap2a mutant named Doarad ( Dor) that has a missense mutation in the PY motif of its transactivation domain, leading to a misshapen malleus, incus, and stapes without any other observable phenotype. Dor homozygous mice die perinatally, showing prominent abnormal facial structures and ocular defects. In vitro assays suggest that this mutation causes a "gain of function" in the transcriptional activation of AP-2alpha. These mice enable us to address more specifically the developmental role of Tcfap2a in the eye and middle ear and are the first report of a mutation in a gene specifically causing middle ear abnormalities, leading to conductive hearing loss.

The deaf mouse mutant Jeff (Jf) is a single gene model of otitis media.

Otitis media is the most common cause of hearing impairment in children and is primarily characterized by inflammation of the middle ear mucosa. Yet nothing is known of the underlying genetic pathways predisposing to otitis media in the human population. Increasingly, large-scale mouse mutagenesis programs have undertaken systematic and genome-wide efforts to recover large numbers of novel mutations affecting a diverse array of phenotypic areas involved with genetic disease including deafness. As part of the UK mutagenesis program, we have identified a novel deaf mouse mutant, Jeff (Jf). Jeff maps to the distal region of mouse chromosome 17 and presents with fluid and pus in the middle ear cavity. Jeff mutants are 21% smaller than wild-type littermates, have a mild craniofacial abnormality, and have elevated hearing thresholds. Middle ear epithelia of Jeff mice show evidence of a chronic proliferative otitis media. The Jeff mutant should prove valuable in elucidating the underlying genetic pathways predisposing to otitis media.

A novel stereocilia defect in sensory hair cells of the deaf mouse mutant Tasmanian devil.

Stereocilia are specialized actin-filled, finger-like processes arrayed in rows of graded heights to form a crescent or W-shape on the apical surface of sensory hair cells. The stereocilia are deflected by the vibration of sound, which opens transduction channels and allows an influx of ions to depolarize the hair cell, in turn triggering synaptic activity. The specialized morphology and organization of the stereocilia bundle is crucial in the process of sensory transduction in the inner ear. However, we know little about the development of stereocilia in the mouse and few molecules that are involved in stereocilia maturation are known. We describe here a new mouse mutant with abnormal stereocilia development. The Tasmanian devil (tde) mouse mutation arose by insertional mutagenesis and has been mapped to the middle of chromosome 5. Homozygotes show head-tossing and circling and have raised thresholds for cochlear nerve responses to sound. The gross morphology of the inner ear was normal, but the stereocilia of cochlear and vestibular hair cells are abnormally thin, and they become progressively disorganized with increasing age. Ultimately, the hair cells die. This is the first report of a mutant showing thin stereocilia. The association of thin stereocilia with cochlear dysfunction emphasizes the critical role of stereocilia in auditory transduction, and the discovery of the Tasmanian devil mutant provides a resource for the identification of an essential molecule in hair cell function.

ENU mutagenesis reveals a highly mutable locus on mouse Chromosome 4 that affects ear morphogenesis.

Chemical mutagenesis followed by screening for abnormal phenotypes in the mouse holds much promise as a method for revealing gene function. This method is particularly well-suited for discovering genes involved in hearing or balance function, as these defects are relatively easy to screen for in the mouse. We report here the inner ear abnormalities and genetic localization of seven new dominant mutations created by ENU mutagenesis. All seven mutant stocks were identified because of circling and/or head-weaving behavior, which is an indication of balance dysfunction. Investigation of the inner ears of the seven mutant stocks revealed very similar lateral and posterior semicircular canal defects. Studies of the development of the canals in one mutant stock revealed that the affected canals showed reduced outgrowth and delayed canal fusion. Physiological studies performed in one mutant stock showed raised average compound-action-potential thresholds of approximately 10-20 dB sound pressure level (SPL) (depending on frequency), indicating a mild hearing impairment, although scanning electron microscopy performed in several of the mutant stocks revealed no obvious structural defects in the organ of Corti. All seven mutations mapped to the proximal portion of Chromosome (Chr) 4, near the centromere. On the basis of their similar phenotype and map location, we suggest that the seven mutant genes may be allelic and represent a highly mutable locus on Chr 4 that may be particularly susceptible to ENU-induced mutation on the BALB/c genetic background.

Beethoven, a mouse model for dominant, progressive hearing loss DFNA36.

Despite recent progress in identifying genes underlying deafness, there are still relatively few mouse models of specific forms of human deafness. Here we describe the phenotype of the Beethoven (Bth) mouse mutant and a missense mutation in Tmc1 (transmembrane cochlear-expressed gene 1). Progressive hearing loss (DFNA36) and profound congenital deafness (DFNB7/B11) are caused by dominant and recessive mutations of the human ortholog, TMC1 (ref. 1), for which Bth and deafness (dn) are mouse models, respectively.