Lancet neurology
-
A growing need exists for reliable in-vivo measurement of neuroinflammation to better characterise the inflammatory processes underlying various diseases and to inform the development of novel therapeutics that target deleterious glial activity. PET is well suited to quantify neuroinflammation and has the potential to discriminate components of the neuroimmune response. However, there are several obstacles to the reliable quantification of neuroinflammation by PET imaging. ⋯ Tissue studies have also begun to clarify the meaning of changes in PET signal in some diseases. Furthermore, although PET imaging of neuroinflammation does not have an established clinical application, novel targets are under investigation and a small but growing number of studies have suggested that this imaging modality could have a role in drug development. Future studies are needed to further improve our knowledge of the cellular mechanisms that underlie changes in PET signal, how immune response contributes to neurological disease, and how it might be therapeutically modified.
-
Randomized Controlled Trial Multicenter Study Comparative Study
Effects of intensive versus standard blood pressure control on domain-specific cognitive function: a substudy of the SPRINT randomised controlled trial.
Results from the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive control of systolic blood pressure significantly reduced the occurrence of mild cognitive impairment, but not probable dementia. We investigated the effects of intensive lowering of systolic blood pressure on specific cognitive functions in a preplanned substudy of participants from SPRINT. ⋯ National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Alzheimer's Association.
-
Huntington's disease is a fatal neurodegenerative disorder that is caused by CAG-CAA repeat expansion, encoding polyglutamine, in the huntingtin (HTT) gene. Current age-of-clinical-onset prediction models for Huntington's disease are based on polyglutamine length and explain only a proportion of the variability in age of onset observed between patients. These length-based assays do not interrogate the underlying genetic variation, because known genetic variants in this region do not alter the protein coding sequence. Given that individuals with identical repeat lengths can present with Huntington's disease decades apart, the search for genetic modifiers of clinical age of onset has become an active area of research. ⋯ Results from three independent genetic studies of Huntington's disease have shown that glutamine-encoding CAA variants that interrupt DNA CAG repeat tracts, but do not alter polyglutamine length or polyglutamine homogeneity, are associated with substantial differences in age of onset of Huntington's disease in carriers. A variant that results in the loss of CAA interruption is associated with early onset and is particularly relevant to individuals that carry alleles in the reduced penetrance range (ie, CAG 36-39). Approximately a third of clinically manifesting carriers of reduced penetrance alleles, defined by current diagnostics, carry this variant. Somatic repeat instability, modified by interrupted CAG tracts, is the most probable cause mediating this effect. This relationship is supported by genome-wide screens for disease modifiers, which have revealed the importance of DNA-repair genes in Huntington's disease (ie, FAN1, LIG1, MLH1, MSH3, PMS1, and PMS2). WHERE NEXT?: Focus needs to be placed on refining our understanding of the effect of the loss-of-interruption and duplication-of-interruption variants and other interrupting sequence variants on age of onset, and assessing their effect in disease-relevant brain tissues, as well as in diverse population groups, such as individuals from Africa and Asia. Diagnostic tests should be augmented or updated, since current tests do not assess the underlying DNA sequence variation, especially when assessing individuals that carry alleles in the reduced penetrance range. Future studies should explore somatic repeat instability and DNA repair as new therapeutic targets to modify age of onset in Huntington's disease and in other repeat-mediated disorders. Disease-modifying therapies could potentially be developed by therapeutically targeting these processes. Promising approaches include therapeutically targeting the expanded repeat or directly perturbing key DNA-repair genes (eg, with antisense oligonucleotides or small molecules). Targeting the CAG repeat directly with naphthyridine-azaquinolone, a compound that induces contractions, and altering the expression of MSH3, represent two viable therapeutic strategies. However, as a first step, the capability of such novel therapeutic approaches to delay clinical onset in animal models should be assessed.