Diagnosing Alzheimer's Disease from Circulating Blood Leukocytes Using a Fluorescent Amyloid Probe

BACKGROUND: Toxic amyloid-β (Aβ) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. OBJECTIVE: To develop a novel method for early Alzheimer's disease (AD) detection, we used blood leukocytes, that could act as "sentinels" after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with confocal spectral microscopy. METHODS: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. RESULTS: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aβ 42 and t-Tau metrics further improved the AUC to 0.93. CONCLUSION: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease

The 2018 report of the Lancet Countdown on health and climate change: shaping the health of nations for centuries to come

The Lancet Countdown: tracking progress on health and climate change was established to provide an independent, global monitoring system dedicated to tracking the health dimensions of the impacts of, and the response to, climate change. The Lancet Countdown tracks 41 indicators across five domains: climate change impacts, exposures, and vulnerability; adaptation, planning, and resilience for health; mitigation actions and health co-benefits; finance and economics; and public and political engagement. This report is the product of a collaboration of 27 leading academic institutions, the UN, and intergovernmental agencies from every continent. The report draws on world-class expertise from climate scientists, ecologists, mathematicians, geographers, engineers, energy, food, livestock, and transport experts, economists, social and political scientists, public health professionals, and. doctors. The Lancet Countdown’s work builds on decades of research in this field, and was first proposed in the 2015 Lancet Commission on health and climate change,1 which documented the human impacts of climate change and provided ten global recommendations to respond to this public health emergency and secure the public health benefits available (panel 1)

Prevalence of mild behavioral impairment in mild cognitive impairment and subjective cognitive decline, and its association with caregiver burden

Background: Mild behavioral impairment (MBI) describes later life acquired, sustained neuropsychiatric symptoms (NPS) in cognitively normal individuals or those with mild cognitive impairment (MCI), as an at-risk state for incident cognitive decline and dementia. We developed an operational definition of MBI and tested whether the presence of MBI was related to caregiver burden in patients with subjective cognitive decline (SCD) or MCI assessed at a memory clinic. Methods: MBI was assessed in 282 consecutive memory clinic patients with SCD (n = 119) or MCI (n = 163) in accordance with the International Society to Advance Alzheimer's Research and Treatment – Alzheimer's Association (ISTAART–AA) research diagnostic criteria. We operationalized a definition of MBI using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Caregiver burden was assessed using the Zarit caregiver burden scale. Generalized linear regression was used to model the effect of MBI domains on caregiver burden. Results: While MBI was more prevalent in MCI (85.3%) than in SCD (76.5%), this difference was not statistically significant (p = 0.06). Prevalence estimates across MBI domains were affective dysregulation (77.8%); impulse control (64.4%); decreased motivation (51.7%); social inappropriateness (27.8%); and abnormal perception or thought content (8.7%). Affective dysregulation (p = 0.03) and decreased motivation (p=0.01) were more prevalent in MCI than SCD patients. Caregiver burden was 3.35 times higher when MBI was present after controlling for age, education, sex, and MCI (p < 0.0001). Conclusions: MBI was common in memory clinic patients without dementia and was associated with greater caregiver burden. These data show that MBI is a common and clinically relevant syndrome.We would like to acknowledge the support of the Ron and Irene Ward foundation, the Taylor family foundation, the Clinician Engagement Grant from the Addiction and Mental Health Strategic Clinical Network of Alberta Health Services, and the Alzheimer’s Society of Calgary, via the Hotchkiss Brain Institute. M. E. Mortby is supported by the Australian National Health and Medical Research Council (NHMRC) and Australian Research Council (ARC) Dementia Research Development Fellowship #1102028

A pragmatic dementia risk score for patients with mild cognitive impairment in a memory clinic population: Development and validation of a dementia risk score using routinely collected data

Abstract Introduction This study aimed to develop and validate a 3‐year dementia risk score in individuals with mild cognitive impairment (MCI) based on variables collected in routine clinical care. Methods The prediction score was trained and developed using data from the National Alzheimer's Coordinating Center (NACC). Selection criteria included aged 55 years and older with MCI. Cox models were validated externally using two independent cohorts from the Prospective Registry of Persons with Memory Symptoms (PROMPT) registry and the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Results Our Mild Cognitive Impairment to Dementia Risk (CIDER) score predicted dementia risk with c‐indices of 0.69 (95% confidence interval [CI] 0.66–0.72), 0.61 (95% CI 0.59–0.63), and 0.72 (95% CI 0.69–0.75), for the internally validated and the external validation PROMPT, and ADNI cohorts, respectively. Discussion The CIDER score could be used to inform clinicians and patients about the relative probabilities of developing dementia in patients with MCI

Final 2 year results of the vascular imaging of acute stroke for identifying predictors of clinical outcome and recurrent ischemic eveNts (VISION) study

<p>Abstract</p> <p>Among patients with ischemic stroke, little attention has been paid to differentiation between stroke progression and recurrence. We assessed the role of MR imaging in predicting stroke progression, recurrent stroke, and death within 2 years of symptom onset.</p> <p>Methods</p> <p>Ischemic stroke or TIA patients were prospectively enrolled. They were examined within 12 hours and had a stroke MR completed within 24 hours of symptom onset. Patients were closely followed neurologically and examined if there was any deterioration in neurological status. Relationships between baseline clinical and imaging factors and outcomes were assessed. We also examined whether baseline stroke/TIA severity (NIHSS 0-5 versus NIHSS > 5) modified these relationships.</p> <p>Results</p> <p>A total of 334 patients were enrolled. The overall rates of progression, 2-year recurrence, and 2-year death were 8.7%, 8.0%, and 6.6%, respectively. Event rates were similar among patients with mild compared to more severe strokes: 8.3% versus 9.5% (p = 0.73) for progression, and 7.3% versus 9.9% (p = 0.59) for recurrence. The effect of baseline glucose > 8 mmol/l was consistent in predicting stroke progression, recurrent stroke and death, regardless of baseline stroke severity. In multivariable analyses, DWI lesion and intracranial occlusion predicted stroke progression only in the minor stroke/TIA group; symptomatic Internal Carotid Artery (ICA) stenosis predicted stroke recurrence only in the minor stroke/TIA group.</p> <p>Conclusions</p> <p>In a prospective study with early assessment and imaging we have found that stroke progression is different than stroke recurrence. Different imaging factors predict stroke progression versus stroke recurrence. Baseline hyperglycemia, a potentially modifiable factor, consistently predicted all three outcomes (stroke progression, recurrent stroke or death) regardless of baseline stroke severity.</p