Generation of a new transgenic mouse model for assessment of tau gene silencing therapies.

BACKGROUND: Targeting the expression of genes has emerged as a potentially viable therapeutic approach to human disease. In Alzheimer's disease, therapies that silence the expression of tau could be a viable strategy to slow disease progression. METHODS: We produced a novel strain of transgenic mice that could be used to assess the efficacy of gene knockdown therapies for human tau, in live mice. We designed a tetracycline-regulated transgene construct in which the cDNA for human tau was fused to ubiquitin and to luciferase to create a single fusion polyprotein, termed TUL. RESULTS: When expressed in brain, the TUL polyprotein was cleaved by ubiquitin-processing enzymes to release the luciferase as an independent protein, separating the half-life of luciferase from the long-lived tau protein. Treatment of bigenic tTA/TUL mice with doxycycline produced rapid declines in luciferase levels visualized by in vivo imaging and ex vivo enzyme measurement. CONCLUSIONS: This new mouse model can be used as a discovery tool in optimizing gene targeting therapeutics directed to reduce human tau mRNA levels.

Corticobasal degeneration: clinical characteristics and multidisciplinary therapeutic approach in 26 patients.

Corticobasal syndrome (CBS) is a sporadic tauopathy that manifests by a various combination of motor and cognitive deficits, which makes its diagnosis challenging. Treatment of CBS is symptomatic and based on evidence from other similar disorders due to the lack of studies on CBS. The aim of the study was to investigate low-frequency repetitive transcranial magnetic stimulation (rTMS) as a therapeutic tool in CBS. Twenty-six patients with clinically evident CBS according to Cambridge criteria were followed for 12-18 months while receiving low-frequency rTMS combined with pharmacological, rehabilitation treatment and botulinum toxin injection. The majority of patients are manifested with akinetic-rigid syndrome and cognitive dysfunction. There was improvement of the UPDRS and quality of life after 3 months of therapeutic interventions (P < 0.001 and <0.05, respectively). No significant deterioration in cognitive functions was detected over the study period. There was a significant reduction of caregiver burden after 3 months of interventions (P < 0.01); this improvement was maintained up to 18 months. Cognitive dysfunction is a frequent manifestation of CBS. CBS patients can benefit from multidisciplinary therapeutic approach employing low-frequency rTMS.

New horizons in the pathogenesis, assessment and management of movement disorders.

In this review, we shall outline recent advances in our understanding of the movement disorders which geriatricians encounter in their clinical practice. Many of these diseases are no longer simply considered disorders of movement: carefully conducted longitudinal studies have shown that concomitant cognitive dysfunction, neuropsychiatric disturbance and behavioural issues are frequent and exert a heavy burden on the individual and their carers. Great progress has been made in understanding the molecular and cellular processes that drive the pathological changes in these conditions, as have advances in neuroimaging and preclinical drug discovery programmes. Unfortunately, this is yet to translate into disease-modifying therapies for these progressive disorders. Advances have been also made in non-pharmacological interventions such as tailored physiotherapy and speech therapy programmes. The important contribution of palliative care has been recognised and increasingly incorporated into the multidisciplinary approach. The UK is at the forefront of research into these conditions and geriatricians are well placed to contribute to research through recruiting patients to observational studies or therapeutic trials, particularly with the support of agencies such as the National Institute for Health Research-Dementias & Neurodegenerative Diseases Research Network (NIHR-DeNDRoN).