Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease

Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively.Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions

Bimetallic Fe–Ir and Trimetallic Fe–Ir–Au Carbonyl Clusters Containing Hydride and/or Phosphine Ligands: Syntheses, Structures and DFT Studies

The reaction of [HFe4(CO)12(IrCOD)]2− (1) with CO at ambient conditions afforded [HFe4Ir(CO)14]2− (2), that, in turn, reacted with HBF4·Et2O affording [Fe4Ir(CO)15]− (3). 1 reacted with a slight excess of PPh3 resulting in a mixture of [HFe2Ir2(CO)10(PPh3)2]− (ca. 37%) (5) and [H2Fe3Ir(CO)10(PPh3)2]− (ca. 63%) (6). 5 and 6 co-crystallized as their [NEt4][H1+xFe2+xIr2-x(CO)10(PPh3)2]·CH2Cl2 (x = 0.63) salt. The reaction of 1 with Au(PPh3)Cl afforded [Fe3Ir(CO)12(AuPPh3)]2− (7). The related hydride [HFe3Ir(CO)12]2− (9) was prepared from the reaction of [HFe4(CO)12]3− (8) with [Ir(COE)2Cl]2 (COE = cyclo-octene). For sake of comparison, [HFe3Co(CO)12]2− (10) was obtained from 8 and Co2(CO)8. All the new clusters have been fully characterized via IR, 1H,13C{1H} and 31P{1H} NMR spectroscopies and their structures determined by means of single crystal X-ray crystallography. Possible isomers have been investigated by DFT calculations

Stable gold(III) catalysts by oxidative addition of a carbon–carbon bond

Whereas low-valent late transition metal catalysis has become indispensible for chemical synthesis, homogeneous high-valent transition metal catalysis is underdeveloped, mainly due to the reactivity of high-valent transition metal complexes and the challenges associated with synthesizing them. In this manuscript, we report a mild carbon-carbon bond cleavage reaction by a Au(I) complex that generates a stable Au(III) cationic complex. Complementary to the well-established soft and carbophilic Au(I) catalyst, this Au(III) complex exhibits hard, oxophilic Lewis acidity. This is exemplified by catalytic activation of α,β-unsaturated aldehydes towards selective conjugate additions as well as activation of an unsaturated aldehyde-allene for a [2 + 2] cycloaddition reaction. The origin of the regioselectivity and catalytic activity was elucidated by X-ray crystallographic analysis of an isolated Au(III)-activated cinnamaldehyde intermediate. The concepts revealed in this study provide a strategy for accessing high-valent transition metal catalysis from readily available precursors. Transition metal catalysis has been developed into an efficient and selective strategy for organic transformations in modern chemistry. Low-valent late transition metal complexe