RESUMO
Multiple system atrophy (MSA) is a progressive neurodegenerative disease in adults, manifesting various clinical symptoms including autonomic nerve dysfunction, Parkinson's syndrome, cerebellar ataxia, and pyramidal sign. The clinical diagnosis and classification of MSA are mainly dependent on motion and non-motion symptoms, such as autonomic nerve dysfunction. In addition, an increasing amount of clinical and pathological evidence has shown that about half of the MSA patients exhibit distinct types and levels of cognitive dysfunction. However, cognitive dysfunction has not been included in the current diagnosis criteria of MSA. In most cases, it was even used as an exclusion criterion of MSA. Based on the neuroimaging, neuropathology and neuropsychology, this review summarized the morphological changes of the brain in the patients with MSA, and discussed possible brain regions that could be associated with cognitive impairment. The article may provide a theoretical basis for incorporating cognitive dysfunction into the criteria of MSA diagnosis.
RESUMO
Small molecule Toll-like receptor 7 (TLR7) agonists have been used as vaccine adjuvants by enhancing innate immune activation to afford better adaptive response. Localized TLR7 agonists without systemic exposure can afford good adjuvanticity, suggesting peripheral innate activation (non-antigen-specific) is not required for immune priming. To enhance colocalization of antigen and adjuvant, benzonaphthyridine (BZN) TLR7 agonists are chemically modified with phosphonates to allow adsorption onto aluminum hydroxide (alum), a formulation commonly used in vaccines for antigen stabilization and injection site deposition. The adsorption process is facilitated by enhancing aqueous solubility of BZN analogs to avoid physical mixture of two insoluble particulates. These BZN-phosphonates are highly adsorbed onto alum, which significantly reduced systemic exposure and increased local retention post injection. This report demonstrates a novel approach in vaccine adjuvant design using phosphonate modification to afford adsorption of small molecule immune potentiator (SMIP) onto alum, thereby enhancing co-delivery with antigen.