Abstract Background The purpose of conducting this study was to identify areas of concordance and sources of variation for the published rates of prevalence and incidence associated with various ...definitions for mild cognitive impairment (MCI). Methods The study used systematic review of studies published in English since 1984. Studies were identified by searching MEDLINE and EMBASE databases. Population-based observational studies of incidence or prevalence of MCI and related terms were eligible for inclusion. Results A total of 3,705 citations were identified, and 42 were accepted for inclusion; 35 included data on prevalence and 13 on incidence. The following four terms predominated: age-associated memory impairment (AAMI); cognitive impairment no dementia (CIND); MCI; and amnestic MCI (aMCI). Within each term, the operational definition varied. Substantial variation was observed for both incidence (MCI: 21.5–71.3; aMCI: 8.5–25.9 per 1,000 person-years) and prevalence of each definition of cognitive impairment (AAMI 3.6%–38.4%; CIND 5.1%–35.9%; MCI 3%–42%; aMCI 0.5%–31.9%). CIND and MCI showed increasing prevalence among older age groups, whereas age-specific rates of aMCI were lower and without any apparent age relationship. Conclusions Prevalence and incidence estimates associated with MCI vary greatly both between definitions and within a definition across the 42 publications. These wide differences pose a significant challenge to our understanding of the social burden of this disease. Enhancement and standardization of operational definitions of the subtypes of cognitive impairment could improve estimates of disease burden and provide a mechanism to assist in the identification of individuals at risk for future Alzheimer’s disease and other dementias.
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FZAB, GEOZS, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBJE, SBMB, UL, UM, UPUK
Aggregation of α-synuclein (α-syn) is neuropathologically and genetically linked to Parkinson's disease (PD). Since stereotypic cell-to-cell spreading of α-syn pathology is believed to contribute to ...disease progression, immunotherapy with antibodies directed against α-syn is considered a promising therapeutic approach for slowing disease progression. Here we report the identification, binding characteristics, and efficacy in PD mouse models of the human-derived α-syn antibody BIIB054, which is currently under investigation in a Phase 2 clinical trial for PD. BIIB054 was generated by screening human memory B-cell libraries from healthy elderly individuals. Epitope mapping studies conducted using peptide scanning, X-ray crystallography, and mutagenesis show that BIIB054 binds to α-syn residues 1–10. BIIB054 is highly selective for aggregated forms of α-syn with at least an 800-fold higher apparent affinity for fibrillar versus monomeric recombinant α-syn and a strong preference for human PD brain tissue. BIIB054 discriminates between monomers and oligomeric/fibrillar forms of α-syn based on high avidity for aggregates, driven by weak monovalent affinity and fast binding kinetics. In efficacy studies in three different mouse models with intracerebrally inoculated preformed α-syn fibrils, BIIB054 treatment attenuated the spreading of α-syn pathology, rescued motor impairments, and reduced the loss of dopamine transporter density in dopaminergic terminals in striatum. The preclinical data reported here provide a compelling rationale for clinical development of BIIB054 for the treatment and prevention of PD.
•Identification of an aggregate selective human-derived antibody to α-synuclein.•BIIB054 shows ≥800-fold higher binding to aggregates than monomer.•Structure activity relationship of the BIIB054/α-synuclein complex.•BIIB054 treatment in mice reduces spread of pathology and improves motor function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
10.
Neuropsychiatric symptoms in Alzheimer’s disease Lyketsos, Constantine G; Carrillo, Maria C; Ryan, J. Michael ...
Alzheimer's & dementia,
September 2011, Volume:
7, Issue:
5
Journal Article, Conference Proceeding
Peer reviewed
Open access
Abstract Neuropsychiatric symptoms (NPS) are core features of Alzheimer’s disease and related dementias. Once thought to emerge primarily in people with late-stage disease, these symptoms are ...currently known to manifest commonly in very early disease and in prodromal phases, such as mild cognitive impairment. Despite decades of research, reliable treatments for dementia-associated NPS have not been found, and those that are in widespread use present notable risks for people using these medications. An Alzheimer’s Association Research Roundtable was convened in the spring of 2010 to review what is known about NPS in Alzheimer’s disease, to discuss classification and underlying neuropathogenesis and vulnerabilities, and to formulate recommendations for new approaches to tailored therapeutics.
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FZAB, GEOZS, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBJE, SBMB, UL, UM, UPUK
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