Amyloid-β, a hallmark of Alzheimer's disease, begins accumulating up to two decades before the onset of dementia, and can be detected in vivo applying amyloid-β positron emission tomography tracers such as carbon-11-labelled Pittsburgh compound-B. A variety of thresholds have been applied in the literature to define Pittsburgh compound-B positron emission tomography positivity, but the ability of these thresholds to detect early amyloid-β deposition is unknown, and validation studies comparing Pittsburgh compound-B thresholds to post-mortem amyloid burden are lacking. In this study we first derived thresholds for amyloid positron emission tomography positivity using Pittsburgh compound-B positron emission tomography in 154 cognitively normal older adults with four complementary approaches: (i) reference values from a young control group aged between 20 and 30 years; (ii) a Gaussian mixture model that assigned each subject a probability of being amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B index uptake; (iii) a k-means cluster approach that clustered subjects into amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B uptake in different brain regions (features); and (iv) an iterative voxel-based analysis that further explored the spatial pattern of early amyloid-β positron emission tomography signal. Next, we tested the sensitivity and specificity of the derived thresholds in 50 individuals who underwent Pittsburgh compound-B positron emission tomography during life and brain autopsy (mean time positron emission tomography to autopsy 3.1 ± 1.8 years). Amyloid at autopsy was classified using Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria, unadjusted for age. The analytic approaches yielded low thresholds (standard uptake value ratiolow = 1.21, distribution volume ratiolow = 1.08) that represent the earliest detectable Pittsburgh compound-B signal, as well as high thresholds (standard uptake value ratiohigh = 1.40, distribution volume ratiohigh = 1.20) that are more conservative in defining Pittsburgh compound-B positron emission tomography positivity. In voxel-wise contrasts, elevated Pittsburgh compound-B retention was first noted in the medial frontal cortex, then the precuneus, lateral frontal and parietal lobes, and finally the lateral temporal lobe. When compared to post-mortem amyloid burden, low proposed thresholds were more sensitive than high thresholds (sensitivities: distribution volume ratiolow 81.0%, standard uptake value ratiolow 83.3%; distribution volume ratiohigh 61.9%, standard uptake value ratiohigh 62.5%) for CERAD moderate-to-frequent neuritic plaques, with similar specificity (distribution volume ratiolow 95.8%; standard uptake value ratiolow, distribution volume ratiohigh and standard uptake value ratiohigh 100.0%). A receiver operator characteristic analysis identified optimal distribution volume ratio (1.06) and standard uptake value ratio (1.20) thresholds that were nearly identical to the a priori distribution volum...

based on the technology described in this manuscript. Drs. Klunk and Mathis are co-inventors of PIB and, as such, have a financial interest in this license agreement. GE Healthcare provided no grant support for this study and had no role in the design or interpretation of results or preparation of this manuscript.

The incidence and severity of cerebrovascular disease (CVD) increase with advancing age, as does the risk of developing Alzheimer's disease (AD). Not surprisingly, heterogeneous forms of CVD may coexist with AD changes in the ‘ageing brain’. These include angiopathies (affecting both large and small arteries) that result from ‘classical’ risk factors (hypertension, smoking and diabetes) and others (cerebral amyloid angiopathy) that are biochemically closely linked to AD. The morphologic consequences of these various vascular diseases are infarcts and/or haemorrhages of varying sizes within the brain, which lead to neurocognitive decline that may mimic AD – though the vascular abnormalities are usually detectable by neuroimaging. More subtle effects of CVD may include neuroinflammation and biochemical ‘lesions’ that have no reliable morphologic correlate and thus escape the attention of even an experienced Neuropathologist. The pathogenesis of hippocampal injury resembling ischaemic change – commonly seen in the brains of geriatric subjects – remains controversial. In recent years, genetically determined forms of microangiopathy (e.g. CADASIL, CARASIL, Trex1‐related microangiopathies, CARASAL, familial forms of cerebral amyloid angiopathy or CAA) have provided interesting cellular and molecular clues to the pathogenesis of sporadic microvascular disease such as arteriolosclerosis and AD‐related CAA.

The diagnosis and treatment of neurosarcoidosis can be very challenging for several reasons. It affects clinically 5%-10% of sarcoidosis patients, but can be found in up to 25% of autopsies. These data reveal that a high percentage of asymptomatic or misdiagnosed cases can be missed at an initial diagnostic approach. Clinical and imaging findings are often non-specific since they can be found in a large number of neurological disorders. Histopathology can also be confounding if not performed by an expert pathologist and not placed in an appropriate clinical context. In this review, we discuss clinical features, laboratory findings, imaging, and histology of neurosarcoidosis, and we report current evidence regarding drug therapy. We conclude that a correct diagnostic approach should include a multidisciplinary evaluation involving clinicians, radiologists, and pathologists and that future studies should evaluate the genetic signature of neurosarcoidosis as they could be helpful in the assessment of this uncommon disease. With head-to-head comparisons of medical treatment for neurosarcoidosis still lacking due to the rarity of the disease and an increasing number of immunomodulating therapies at hand, novel therapeutic approaches are to be expected within the next few years. Key messages Neurosarcoidosis is a rare disorder that affects clinically 5%-10% of sarcoidosis patients, but can be found in up to 25% of autopsies, revealing that a high percentage of asymptomatic or misdiagnosed cases can be missed at an initial diagnostic approach. A multidisciplinary evaluation is useful to achieve a correct diagnosis because clinical and imaging findings are often non-specific. Corticosteroids are the first-line treatment for neurosarcoidosis, followed by steroid-sparing immune-modulating agents if prednisone therapy is insufficient. Dear Author, Please check these proofs carefully. It is the responsibility of the corresponding author to check against the original manuscript and approve or amend these proofs. A second proof is not normally provided. Informa Healthcare cannot be held responsible for uncorrected errors, even if introduced during the composition process. The journal reserves the right to charge for excessive author alterations, or for changes requested after the proofing stage has concluded.The following queries have arisen during the editing of your manuscript and are marked in the margins of the proofs. Unless advised otherwise, submit all corrections using the CATS online correction form. Once you have added all your corrections, please ensure you press the ''Submit All Corrections'' button.Please review the table of contributors below and confirm that the first and last names are structured correctly and that the authors are listed in the correct order of contribution. The diagnosis and treatment of neurosarcoidosis can be very challenging for several reasons. It affects clinically 5%-10% of sarcoidosis patients, but can be found in up to 25% of autopsies. These data reveal that a high percenta...

Amyloid-beta related angiitis (ABRA) of the central nervous system (CNS) is a rare disorder with overlapping features of primary angiitis of the CNS and cerebral amyloid angiopathy. We evaluated a 74-year-old man with intermittent left sided weakness and MRI findings of leptomeningeal enhancement, vasogenic edema, and subcortical white matter disease proven to have ABRA. We discuss clinicopathological features and review the topic of ABRA.

Case reports of acute kidney injury in patients taking the glucagon-like peptide 1 (GLP-1) receptor agonists exenatide and liraglutide have been reported. We report 2 patients with chronic kidney disease due to diabetic kidney disease who experienced rapid worsening of kidney function and increased proteinuria after being prescribed the GLP-1 receptor agonist semaglutide. In 1 patient, kidney biopsy showed advanced diffuse and nodular glomerulosclerosis accompanied by interstitial lymphoplasmacytic and eosinophilic infiltrate and evidence of acute tubular injury. At this time, the long-term outcomes of patients who experience acute kidney injury associated with GLP-1 receptor agonists is not known. We recommend that caution be used with these agents in patients with moderate to severe chronic kidney disease due to limited kidney reserve in the event of an adverse kidney event. Because most adverse kidney events have occurred in patients who experience adverse gastrointestinal symptoms, such patients should have laboratory tests and discontinuation of the medication if there is acute worsening of kidney function.

Pathologists can have complementary assessments and focus areas when identifying and labeling neuropathologies. A standardized approach would ideally draw on the expertise of the entire cohort. We present a deep learning (DL) framework that consistently labels cored, diffuse, and cerebral amyloid angiopathy (CAA) neuropathologies using expert consensus. We collected 100,495 annotations, comprising 20,099 candidate neuropathologies from three institutions, independently annotated by five experts. We compared DL methods that learned the annotation behaviors of individual experts (AUPRC=0.67±0.06 cored; 0.48±0.06 CAA) versus those that reproduced expert consensus, yielding 8.9-13% improvements (AUPRC=0.73±0.03 cored; 0.54±0.06 CAA). Saliency mapping on neuropathologies illustrated how human expertise may progress from novice to expert. In blind prospective tests of 52,555 subsequently expert-annotated images, the models accurately labeled pathologies similar to their human counterparts (consensus model AUPRC=0.73 cored; 0.68 CAA).

Six series of structurally different mono-and binuclear copper(II) complexes 5-10 were obtained by reacting N- (2-pyridyl)imidazolidin-2-ones (1a-l), N,N'-bis(2-pyridyl)imidazolidin-2-ones (2a,b), N-acyl-N'(2-pyridyl)imidazolodin-2-ones (3a-j) and N-(2-pyridyl)imidazolidine-2-thiones (4a-g) with copper(II) chloride at an ambient temperature. The coordination modes of the complexes obtained were established by elemental analysis, IR spectroscopic data and single crystal X-ray diffraction studies. The in vitro cytotoxic activities of both the free ligands and copper(II) complexes were evaluated using a crystal violet microtiter plate assay on five human tumor cell lines: LCLC-103H, A-427, SISO, RT-4 and DAN-G. The free ligands 1-4 at concentration attainable in cancer cells of 20 μM showed no meaningful cytotoxic effect with cell viability in the range of 88%-100%. The most potent copper(II) complex of 1-(6-ethoxy-2-pyridyl)imidazolidin-2-one (6b) exhibited selective cytotoxicity against A-427 lung cancer cell line, while the complexes of 1-(5-methyl-2-pyridyl)imidazolidine-2-thione (5h) and OPEN ACCESSMolecules 2014, 19 17027 1-(4-tert-butyl-2-pyridyl)imidazolidine-2-thione (5j) showed cytostatic effect against a whole panel of five human tumor cell lines. In conclusion, the only complexes that showed remarkably increased activity in comparison to the free ligands were those obtained from N-(2-pyridyl)imidazolidine-2-thiones 4c and 4e substituted with alkyl group at position 4 or 5 of pyridine ring.