抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Objectives: To develop a 10-minute cognitive screening tool (Montreal Cognitive Assessment, MoCA) to assist first-line physicians in detection of mild cognitive impairment (MCI), a clinical state that often progresses to dementia.

Design: Validation study.

Setting: A community clinic and an academic center.

Participants: Ninety-four patients meeting MCI clinical criteria supported by psychometric measures, 93 patients with mild Alzheimer's disease (AD) (Mini-Mental State Examination (MMSE) score≥17), and 90 healthy elderly controls (NC).

Measurements: The MoCA and MMSE were administered to all participants, and sensitivity and specificity of both measures were assessed for detection of MCI and mild AD.

Results: Using a cutoff score 26, the MMSE had a sensitivity of 18% to detect MCI, whereas the MoCA detected 90% of MCI subjects. In the mild AD group, the MMSE had a sensitivity of 78%, whereas the MoCA detected 100%. Specificity was excellent for both MMSE and MoCA (100% and 87%, respectively).

Conclusion: MCI as an entity is evolving and somewhat controversial. The MoCA is a brief cognitive screening tool with high sensitivity and specificity for detecting MCI as currently conceptualized in patients performing in the normal range on the MMSE.

/pdf/the-montreal-cognitive-assessment-moca-a-brief-screening-4w06t9e7qy.pdf

The Montreal Cognitive Assessment, MoCA: A Brief Screening Tool For Mild Cognitive Impairment

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

/pdf/the-diagnosis-of-dementia-due-to-alzheimer-s-disease-w5k0egjbz5.pdf

The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease

Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

The concept of cognitive impairment intervening between normal ageing and very early dementia has been in the literature for many years. Recently, the construct of mild cognitive impairment (MCI) has been proposed to designate an early, but abnormal, state of cognitive impairment. MCI has generated a great deal of research from both clinical and research perspectives. Numerous epidemiological studies have documented the accelerated rate of progression to dementia and Alzheimer's disease (AD) in MCI subjects and certain predictor variables appear valid. However, there has been controversy regarding the precise definition of the concept and its implementation in various clinical settings. Clinical subtypes of MCI have been proposed to broaden the concept and include prodromal forms of a variety of dementias. It is suggested that the diagnosis of MCI can be made in a fashion similar to the clinical diagnoses of dementia and AD. An algorithm is presented to assist the clinician in identifying subjects and subclassifying them into the various types of MCI. By refining the criteria for MCI, clinical trials can be designed with appropriate inclusion and exclusion restrictions to allow for the investigation of therapeutics tailored for specific targets and populations.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1365-2796.2004.01388.x

Mild cognitive impairment as a diagnostic entity

OBJECTIVE: This study was designed to test the interaction between amyloid-β and tau proteins as a determinant of metabolic decline in preclinical Alzheimer’s disease.
BACKGROUND: A growing body of literature proposes that a synergism between amyloid-β and tau aggregates drives the pathophysiological progression of Alzheimer’s disease.
DESIGN/METHODS: We assessed 120 cognitively normal subjects with [18F]florbetapir and [18F]fluorodeoxyglucose positron emission tomography as well as cerebrospinal fluid phosphorylated tau and total tau at baseline and at 24 months. A voxel-based interaction model was built to test the associations between continuous measurements of cerebrospinal fluid biomarkers, [18F]florbetapir and [18F]fluorodeoxyglucose standardized uptake value ratios.
RESULTS: We found that the synergistic interaction between [18F]florbetapir standardized uptake value ratio and cerebrospinal fluid phosphorylated tau measurements, rather than the sum of their independent effects, was associated with a 24-month metabolic decline in basal and mesial temporal, orbitofrontal, and anterior and posterior cingulate cortices (p<0.001). We also found that the interaction between [18F]florbetapir standardized uptake value ratio and cerebrospinal fluid total tau did not associate with metabolic decline over a time frame of 24 months.
CONCLUSIONS: The interaction found in this study further support the framework that amyloid-β and hyperphosphorylated tau aggregates synergistically interact to cause downstream Alzheimer’s disease neurodegeneration. In fact, the regions displaying the metabolic decline reported here were confined to brain networks affected early by amyloid-β plaques and neurofibrillary tangles. Preventive clinical trials may benefit from using a combination of amyloid-β positron emission tomography and phosphorylated tau biomarkers to enrich study populations of cognitively normal subjects with a high probability of disease progression in studies using [18F]fluorodeoxyglucose as a biomarker of efficacy. Disclosure: Dr. Pascoal has nothing to disclose. Dr. Mathotaarachchi has nothing to disclose. Dr. Benedet has nothing to disclose. Dr. Beaudry has nothing to disclose. Dr. Gauthier has received personal compensation for activities with Neurochem and BELLUS Health Inc. as a member of their scientific advisory board. Dr. Rosa Neto has nothing to disclose.

Amyloid-β and Hyperphosphorylated tau Synergy Drives Metabolic Decline in Preclinical Alzheimer’s Disease (P4.020)

A quadratic function of activation in individuals at risk of Alzheimer's disease.

/pdf/global-estimates-of-informal-care-3x4ehlqje9.pdf

Global estimates of informal care

Drugs acting on the cholinergic system can improve or worsen cognitive abilities, and their effects are particularly pronounced in frail elderly individuals and patients with Alzheimer disease. Guidelines are urgently needed on the judicious use of cholinergic drugs.

Serge Gauthier

Papers

Amyloid-β and Hyperphosphorylated tau Synergy Drives Metabolic Decline in Preclinical Alzheimer’s Disease (P4.020)

A quadratic function of activation in individuals at risk of Alzheimer's disease.

Global estimates of informal care

Alzheimer disease: clinical use of cholinergic drugs in Alzheimer disease.

Modulation of γ-actin and α1-tubulin expression by corticosterone during neuronal plasticity in the hippocampus