Alzheimer's disease, the commonest cause of dementia, is a growing global health concern with huge implications for individuals and society. In this review, current understanding of the epidemiology, genetics, pathology and pathogenesis of Alzheimer's disease is outlined, before its clinical presentation and current treatment strategies are discussed. Finally, the review discusses how our enhanced understanding of Alzheimer pathogenesis, including the recognition of a protracted preclinical phase, is informing new therapeutic strategies with the aim of moving from treatment to prevention.

BackgroundIncreasing age is the biggest risk factor for dementia, of which Alzheimer’s disease is the commonest cause. The pathological changes underpinning Alzheimer’s disease are thought to develop at least a decade prior to the onset of symptoms. Molecular positron emission tomography and multi-modal magnetic resonance imaging allow key pathological processes underpinning cognitive impairment – including β-amyloid depostion, vascular disease, network breakdown and atrophy – to be assessed repeatedly and non-invasively. This enables potential determinants of dementia to be delineated earlier, and therefore opens a pre-symptomatic window where intervention may prevent the onset of cognitive symptoms.Methods/designThis paper outlines the clinical, cognitive and imaging protocol of “Insight 46”, a neuroscience sub-study of the MRC National Survey of Health and Development. This is one of the oldest British birth cohort studies and has followed 5362 individuals since their birth in England, Scotland and Wales during one week in March 1946. These individuals have been tracked in 24 waves of data collection incorporating a wide range of health and functional measures, including repeat measures of cognitive function. Now aged 71 years, a small fraction have overt dementia, but estimates suggest that ~1/3 of individuals in this age group may be in the preclinical stages of Alzheimer’s disease. Insight 46 is recruiting 500 study members selected at random from those who attended a clinical visit at 60–64 years and on whom relevant lifecourse data are available. We describe the sub-study design and protocol which involves a prospective two time-point (0, 24 month) data collection covering clinical, neuropsychological, β-amyloid positron emission tomography and magnetic resonance imaging, biomarker and genetic information. Data collection started in 2015 (age 69) and aims to be completed in 2019 (age 73).DiscussionThrough the integration of data on the socioeconomic environment and on physical, psychological and cognitive function from 0 to 69 years, coupled with genetics, structural and molecular imaging, and intensive cognitive and neurological phenotyping, Insight 46 aims to identify lifetime factors which influence brain health and cognitive ageing, with particular focus on Alzheimer’s disease and cerebrovascular disease. This will provide an evidence base for the rational design of disease-modifying trials.

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Recent studies have led to a satisfactory understanding of the details of acoustical streaming in the vicinity of a cylinder. Similar studies have now been completed for a sphere. In general, the steady flow around a sphere and the characteristic parameters are very much like what has been found for the cylinder. An experimental verification of the theory has been attempted by comparing the observed dc boundary-layer thickness with that found from the theory. This is summarized in a curve of δdc/δac vs a/δac, where δdc is the dc boundary-layer thickness, δac is the ac boundary-layer thickness, and a is the radius of the sphere.

BackgroundHearing impairment may be a modifiable risk factor for dementia. However, it is unclear how hearing associates with pathologies relevant to dementia in preclinical populations.MethodsData from 368 cognitively healthy individuals born during 1 week in 1946 (age range 69.2–71.9 years), who underwent structural MRI, 18F-florbetapir positron emission tomography, pure tone audiometry and cognitive testing as part of a neuroscience substudy the MRC National Survey of Health and Development were analysed. The aim of the analysis was to investigate whether pure tone audiometry performance predicted a range of cognitive and imaging outcomes relevant to dementia in older adults.ResultsThere was some evidence that poorer pure tone audiometry performance was associated with lower primary auditory cortex thickness, but no evidence that it predicted in vivo β-amyloid deposition, white matter hyperintensity volume, hippocampal volume or Alzheimer’s disease-pattern cortical thickness. A negative association between pure tone audiometry and mini-mental state examination score was observed, but this was no longer evident after excluding a test item assessing repetition of a single phrase.ConclusionPure tone audiometry performance did not predict concurrent β-amyloid deposition, small vessel disease or Alzheimer’s disease-pattern neurodegeneration, and had limited impact on cognitive function, in healthy adults aged approximately 70 years.

LEXION-DISTRACTION injuries include facet fractures, subluxations, and dislocations and represent a spectrum of injury severity and instability. 3 Recommendations for surgical treatment of these injuries in the cervical spine remain controversial. In most cases ACFP or posterior fixation alone appear to be sufficient; however, 1,2,[4][5][6]17,24,32 this is not so in other cases. 4,6,9,17 Combined anterior-posterior procedures have been reported to produce successful results; 1,21,23,27,29,30,35 however, clinical experience suggests that combined anterior-posterior stabilization performed for every cervical injury would result in overtreatment in a relevant number of cases. 6,24 Apart from opinion and anecdotal evidence there are no guidelines as to when ACFP alone will provide sufficient stabilization for various posterior element injuries.Biomechanical studies can provide insight into instances in which anterior or posterior fixation alone may not be sufficient. Authors of several biomechanical stud- J Neurosurg (Spine 1) 99:84-90, 2003Object: The primary goal of this study was to determine if the stabilization provided to the spine by anterior cervical fixation with plating (ACFP) was dependent on the degree of posterior element injury. The secondary goal was to evaluate the effectiveness of additional posterior screw/rod stabilization in these injuries.Methods. Following ACFP with interbody bone graft and stepwise transection of the posterior ligaments and facets at C5-6, eight fresh-frozen human C4-7 spine segments were loaded using pure moments of Ϯ 1.5 Nm in flexion-extension, axial rotation, and lateral bending in the intact state. Posterior screw/rod fixation was performed after complete ligamentous destruction and complete removal of the facets. Repeated-measures analysis of variance and pairwise Student-Newman-Keuls tests were used to detect changes in the range of motion (ROM) and neutral zone (NZ). Statistical significance was assumed at a 95% level.Significant increases in ROM occurred in each loading direction after transection of the capsular ligaments (p Ͻ 0.001) and again following facetectomy (p Ͻ 0.001) compared with the ACFP condition. Additional posterior fixation resulted in a significant decrease in ROM in all loading directions (p Ͻ 0.001). There was a significant increase in NZ for complete ligamentous destruction compared with ACFP (p Ͻ 0.05) and facetectomy compared with ACFP (p Ͻ 0.05) for flexion-extension. In lateral bending, a significant increase in NZ was found for facetectomy compared with ACFP (p Ͻ 0.05).Conclusions. Capsular ligaments and articular facets are important structures in limiting three-dimensional vertebral motion in the presence of an anterior plate. Supplementary posterior fixation does reduce motion for all injury conditions. KEY WORDS • cervical spine • biomechanics • ligament • implants • injuryF J. Neurosurg: Spine / Volume 99 / July, 2003 Abbreviations used in this paper: ACFP = anterior cervical fixation and plating; MR = magnetic resonance; NZ = neutral zon...

Classification and differentiation of small pathological objects may greatly vary among human raters due to differences in training, expertise and their consistency over time. In a radiological setting, objects commonly have high within-class appearance variability whilst sharing certain characteristics across different classes, making their distinction even more difficult. As an example, markers of cerebral small vessel disease, such as enlarged perivascular spaces (EPVS) and lacunes, can be very varied in their appearance while exhibiting high inter-class similarity, making this task highly challenging for human raters. In this work, we investigate joint models of individual rater behaviour and multirater consensus in a deep learning setting, and apply it to a brain lesion object-detection task. Results show that jointly modelling both individual and consensus estimates leads to significant improvements in performance when compared to directly predicting consensus labels, while also allowing the characterization of human-rater consistency.

Objective: To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD).Methods: Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty-one participants completed at least 1 follow-up neuropsychological evaluation. Four composite cognitive measures representing global cognition, episodic memory, language, and working memory were generated using z scores from a battery of 13 standard neuropsychological tests. General linear mixed-effects models were used to investigate the relationship between baseline cerebral amyloidosis and baseline cognitive performance and whether baseline cerebral amyloidosis predicts cognitive change over time (mean follow-up 2.32 years 6 0.92, range 0.89-4.19) after controlling for estimated years from expected symptom onset, APOE e4 allelic status, and education.Results: In asymptomatic mutation carriers, amyloid burden was not associated with baseline cognitive functioning but was significantly predictive of longitudinal decline in episodic memory. In symptomatic mutation carriers, cerebral amyloidosis was correlated with worse baseline performance in multiple cognitive composites and predicted greater decline over time in global cognition, working memory, and Mini-Mental State Examination.Conclusions: Cerebral amyloidosis predicts longitudinal episodic memory decline in presymptomatic ADAD and multidomain cognitive decline in symptomatic ADAD. These findings imply that amyloidosis in the brain is an indicator of early cognitive decline and provides a useful outcome measure for early assessment and prevention treatment trials. b-Amyloid (Ab) is thought to be an initiating factor in the pathophysiologic process of Alzheimer disease (AD).1,2 However, the relationship between cognition, brain Ab burden, and the future development of dementia is still unclear.