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Clinical investigations have established that vascular-associated medical conditions are significant risk factors for various kinds of dementia. And yet, we are unable to associate certain types of vascular deficiencies with specific cognitive impairments. The reasons for this are many, not the least of which are that most vascular disorders are multi-factorial and the development of vascular dementia in humans is often a multi-year or multi-decade progression. To better study vascular disease and its underlying causes, the National Heart, Lung, and Blood Institute of the National Institutes of Health has invested considerable resources in the development of animal models that recapitulate various aspects of human vascular disease. Many of these models, mainly in the mouse, are based on genetic mutations, frequently using single-gene mutations to examine the role of specific proteins in vascular function. These models could serve as useful tools for understanding the association of specific vascular signaling pathways with specific neurological and cognitive impairments related to dementia. To advance the state of the vascular dementia field and improve the information sharing between the vascular biology and neurobehavioral research communities, National Heart, Lung, and Blood Institute convened a workshop to bring in scientists from these knowledge domains to discuss the potential utility of establishing a comprehensive phenotypic cognitive assessment of a selected set of existing mouse models, representative of the spectrum of vascular disorders, with particular attention focused on age, sex, and rigor and reproducibility. The workshop highlighted the potential of associating well-characterized vascular disease models, with validated cognitive outcomes, that can be used to link specific vascular signaling pathways with specific cognitive and neurobehavioral deficits.

Background: Cognitive impairment, including dementia, is frequently under-detected in primary care. The Consortium for Detecting Cognitive Impairment, including Dementia (DetectCID) convenes three multidisciplinary teams that are testing novel paradigms to improve the frequency and quality of patient evaluations for detecting cognitive impairment in primary care and appropriate follow-up., Objective: Our objective was to characterize the three paradigms, including similarities and differences, and to identify common key lessons from implementation., Methods: A qualitative evaluation study with dementia specialists who were implementing the detection paradigms. Data was analyzed using content analysis., Results: We identified core components of each paradigm. Key lessons emphasized the importance of engaging primary care teams, enabling primary care providers to diagnose cognitive disorders and provide ongoing care support, integrating with the electronic health record, and ensuring that paradigms address the needs of diverse populations., Conclusion: Approaches are needed that address the arc of care from identifying a concern to post-diagnostic management, are efficient and adaptable to primary care workflows, and address a diverse aging population. Our work highlights approaches to partnering with primary care that could be useful across specialties and paves the way for developing future paradigms that improve differential diagnosis of symptomatic cognitive impairment, identifying not only its presence but also its specific syndrome or etiology.

Traumatic brain injury (TBI) is a risk factor for later-life dementia. Clinical and pre-clinical studies have elucidated multiple mechanisms through which TBI may influence or exacerbate multiple pathological processes underlying Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD). The National Institutes of Health hosts triennial ADRD Summits to inform a national research agenda, and the 2019 ADRD Summit was the first to highlight "TBI and AD/ADRD Risk" as an emerging topic in the field. A multidisciplinary committee of TBI researchers with relevant expertise reviewed extant literature, identified research gaps and opportunities, and proposed draft research recommendations at the 2019 ADRD Summit. These research recommendations, further refined after broad stakeholder input at the Summit, cover four overall areas: 1) Encourage crosstalk and interdisciplinary collaboration between TBI and dementia researchers; 2) Establish infrastructure to study TBI as a risk factor for AD/ADRD; 3) Promote basic and clinical research examining the development and progression of TBI AD/ADRD neuropathologies and associated clinical symptoms; and 4) Characterize the clinical phenotype of progressive dementia associated with TBI and develop non-invasive diagnostic approaches. These recommendations recognize a need to strengthen communication and build frameworks to connect the complexity of TBI with rapidly evolving AD/ADRD research. Recommendations acknowledge TBI as a clinically and pathologically heterogeneous disease whose associations with AD/ADRDs remain incompletely understood. The recommendations highlight the scientific advantage of investigating AD/ADRD in the context of a known TBI exposure, the study of which can directly inform on disease mechanisms and treatment targets for AD/ADRDs with shared common pathways.

Introduction: Many consequences of cerebrovascular disease are identifiable by magnetic resonance imaging (MRI), but variation in methods limits multicenter studies and pooling of data. The European Union Joint Program on Neurodegenerative Diseases (EU JPND) funded the HARmoNizing Brain Imaging MEthodS for VaScular Contributions to Neurodegeneration (HARNESS) initiative, with a focus on cerebral small vessel disease., Methods: Surveys, teleconferences, and an in-person workshop were used to identify gaps in knowledge and to develop tools for harmonizing imaging and analysis., Results: A framework for neuroimaging biomarker development was developed based on validating repeatability and reproducibility, biological principles, and feasibility of implementation. The status of current MRI biomarkers was reviewed. A website was created at www.harness-neuroimaging.org with acquisition protocols, a software database, rating scales and case report forms, and a deidentified MRI repository., Conclusions: The HARNESS initiative provides resources to reduce variability in measurement in MRI studies of cerebral small vessel disease.

Objective: The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems., Methods: Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems., Results: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54-0.58)., Conclusion: Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner., (© 2014 American Academy of Neurology.)

Genome-wide association studies (GWAS) are widely applied to identify susceptibility loci for a variety of diseases using genotyping arrays that interrogate known polymorphisms throughout the genome. A particular strength of GWAS is that it is unbiased with respect to specific genomic elements (e.g., coding or regulatory regions of genes), and it has revealed important associations that would have never been suspected based on prior knowledge or assumptions. To date, the discovered SNPs associated with complex human traits tend to have small effect sizes, requiring very large sample sizes to achieve robust statistical power. To address these issues, a number of efficient strategies have emerged for conducting GWAS, including combining study results across multiple studies using meta-analysis, collecting cases through electronic health records, and using samples collected from other studies as controls that have already been genotyped and made publicly available (e.g., through deposition of de-identified data into dbGaP or EGA). In certain scenarios, it may be attractive to use already genotyped controls and divert resources to standardized collection, phenotyping, and genotyping of cases only. This strategy, however, requires that careful attention be paid to the choice of "public controls" and to the comparability of genetic data between cases and the public controls to ensure that any allele frequency differences observed between groups is attributable to locus-specific effects rather than to a systematic bias due to poor matching (population stratification) or differential genotype calling (batch effects). The goal of this paper is to describe some of the potential pitfalls in using previously genotyped control data. We focus on considerations related to the choice of control groups, the use of different genotyping platforms, and approaches to deal with population stratification when cases and controls are genotyped across different platforms.

Intrinsic antioxidant defenses are important for neuronal longevity. We found that in rat neurons, synaptic activity, acting via NMDA receptor (NMDAR) signaling, boosted antioxidant defenses by making changes to the thioredoxin-peroxiredoxin (Prx) system. Synaptic activity enhanced thioredoxin activity, facilitated the reduction of overoxidized Prxs and promoted resistance to oxidative stress. Resistance was mediated by coordinated transcriptional changes; synaptic NMDAR activity inactivated a previously unknown Forkhead box O target gene, the thioredoxin inhibitor Txnip. Conversely, NMDAR blockade upregulated Txnip in vivo and in vitro, where it bound thioredoxin and promoted vulnerability to oxidative damage. Synaptic activity also upregulated the Prx reactivating genes Sesn2 (sestrin 2) and Srxn1 (sulfiredoxin), via C/EBPbeta and AP-1, respectively. Mimicking these expression changes was sufficient to strengthen antioxidant defenses. Trans-synaptic stimulation of synaptic NMDARs was crucial for boosting antioxidant defenses; chronic bath activation of all (synaptic and extrasynaptic) NMDARs induced no antioxidative effects. Thus, synaptic NMDAR activity may influence the progression of pathological processes associated with oxidative damage.

The objective of this multicentre, randomised, open-label, general practice (GP) study was to evaluate the efficacy and tolerability of cefprozil (Cefzil(trade mark), Bristol-Myers Squibb) compared with that of cefuroxime axetil (Ceftin((R)), Glaxo Wellcome) in the treatment of adult subjects with acute sinusitis. Typical of the GP setting, diagnosis was made based solely on clinical signs and symptoms of acute disease. Sinus radiography was performed post-randomisation. A total of 381 adolescent and adult patients were randomly assigned to 10 days' treatment with either cefprozil, 500mg orally twice daily (n = 191), or cefuroxime axetil, 250mg orally twice daily (n = 190). Based on predefined criteria, treatments were found to be equally effective in terms of proportions of patients in the per-protocol population that were cured, improved or failed (p = 0.20). Similar results were observed when the evaluation was performed on the subset of patients with radiographic evidence of sinusitis and when the evaluation was based on the investigator's judgement. Similar rates of adverse events were observed in the two treatment groups. In summary, cefprozil 500mg twice daily is as well tolerated and as effective as cefuroxime axetil 250mg twice daily for the treatment of adolescent and adult patients with clinical signs and symptoms of acute sinusitis.