Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

IntroductionLarge variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways.MethodsGenome Research at Fundacio ACE ([email protected]) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, [email protected] series were meta-analyzed with additional genome-wide association study data sets.ResultsWe classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444.DiscussionThe regulation of vasculature is a prominent causal component of probable AD. [email protected] meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.     

Long-Term Follow-Up of Cerebral Amyloid Angiopathy-Associated Intracranial Hemorrhage Reveals a High Prevalence of Atrial Fibrillation

Goal: Cerebral amyloid angiopathy (CAA) is the second-most common cause of nontraumatic intracerebral hemorrhages (ICH), surpassed only by uncontrolled hypertension. We characterized the percentage, risk factors, and comorbidities of patients suffering from CAA-related ICH in relation to long-term outcomes. Material and Methods: We performed retrospective analyses and clinical follow-ups of individuals suffering from ICH who were directly admitted to neurosurgery between 2002 and 2016. Findings: Seventy-four of 174 (42%) spontaneous nontraumatic lobar ICH cases leastwise satisfied the modified Boston criteria definition for at least “possible CAA.” Females suffered a higher risk of CAA-caused ICH (42 of 74, 56.8%, P= .035). Atrial fibrillation as a major comorbidity was observed in 19 patients (25.7%). Recovery (decrease of modified Rankin scale [mRS]) was highest during hospitalization in the acute clinic. One-year mortality was as follows: 14 of 25 patients (56%) with probable CAA without supporting pathology, 6 of 18, and 8 of 31 patients with supporting pathology and possible CAA, respectively. Only 10 of 74 (13.6%) had favorable long-term outcomes (mRS ≤2). Increasing numbers of lobar hemorrhages, low initial Glasgow Coma Scale, and subarachnoid hemorrhage were significantly associated with poor survivability, whereas statins, antithrombotic agents, an intraventricular hemorrhage, and midline shift played seemingly minor roles. Conclusions: Symptomatic ICH is a serious stage in CAA progression with high mortality. The high incidence of concurrent atrial fibrillation in these patients may support data on more widespread vascular pathology in CAA.     

Small Cortical Infarcts Transformed to Lobar Cerebral Microbleeds: A Case Series

Cerebral microbleeds (MBs) have been often observed due to the development of imaging devices, and are classified to deep and lobar MBs. Lobar MBs are strongly associated with cerebral amyloid angiopathy. Here, we report 3 cases of lobar MBs that developed after small cortical ischemic stroke. One case underwent carotid artery stenting for severe carotid stenosis, one was diagnosed with artery-to-artery embolism, and the other was embolic stroke of undetermined source. New small cortical infarctions were detected with diffusion-weighted magnetic resonance imaging (MRI). Initial MRI revealed no hemorrhage around the ischemic lesion on T2*-weighted gradient-recalled echo or susceptibility-weighted imaging (SWI) at the onset of stroke. Follow-up SWI after 12-20 months revealed lobar MBs in the previously detected ischemic lesions, and high-intensity lesions remained around the MBs on fluid-attenuated inversion recovery imaging. These cases revealed that cerebral MBs developed through the transformation of small cortical infarctions. All cases showed lobar MBs, and these MBs existed in the previously detected ischemic lesions at a chronic stage. Lobar MBs present around ischemic lesions may predict embolic infarcts.     

脑淀粉样血管病发病机制的研究进展

脑淀粉样血管病（cerebral amyloid angiopathy，CAA）的主要致病物质是β淀粉样蛋白，其 产生异常、清除障碍导致异常沉积，引起管壁破坏、管腔狭窄等病理变化，最终导致CAA。目前CAA的 具体发病机制尚不清楚，涉及的成分复杂。本文介绍了β淀粉样蛋白产生及清除的三种过程及其平 衡破坏的后续效应和主要影响因素，同时从病因分类的角度阐明CAA的类型。     

糖尿病肾病患者认知功能障碍与血清β淀粉样蛋白的关系

目的 探讨糖尿病肾病(diabetic kidney disease,DKD)患者认知功能障碍与人β淀粉样蛋白1-42(human β Amyloid 1-42,Aβ1-42)的关系。方法 选取2020年5月至2021年5月在徐州医科大学附属医院内分泌科治疗的2型糖尿病(type 2 diabetes mellitus,T2DM)患者161例,根据尿白蛋白/肌酐比值(urine albumin creatine ratio,UACR)水平分为正常白蛋白尿(DM)组(n=60)、微量白蛋白尿(DKD1)组(n=58)和大量白蛋白尿(DKD2)组(n=43)。采用蒙特利尔认知评估(Montreal Cognitive Assessment,MoCA)量表评估患者认知功能。检测患者Aβ1-42、UACR、胱抑素C(Cystatin C,CysC)、估算肾小球滤过率(estimated glomerular filtration rate,eGFR),并分析上述指标与MoCA评分的关系。结果 与DM组比较,DKD1和DKD2组CysC、Aβ1-42均升高(P<0.05),eGFR降低(P<0.05)。与DKD1组比较,DKD2组CysC升高(P<0.05),eGFR降低(P<0.05)。与DM组相比,DKD1组、DKD2组MoCA评分均降低(P<0.05)。与DKD1组比较,DKD2组MoCA评分降低(P<0.05)。3组MoCA评分与Aβ1-42、UACR、CysC呈负相关(均P<0.01),与eGFR呈正相关(P<0.01)。3组Aβ1-42与UACR、CysC呈正相关(均P<0.01),与eGFR呈负相关(P<0.01)。多因素线性回归分析结果显示,Aβ1-42、UACR是影响DKD患者MoCA评分的影响因素,Aβ1-42、UACR水平越高,MoCA评分越低,患者认知功能越差。结论 DKD患者存在认知功能障碍,与Aβ1-42水平及肾损害严重程度密切相关。     

Age-related amyloidosis outside the brain: A state-of-the-art review

Inside and outside the brain, accumulation of amyloid fibrils plays key roles in the pathogenesis of fatal age-related diseases such as Alzheimer’s and Parkinson’s diseases and wild-type transthyretin amyloidosis. Although the incidence of all amyloidoses increases with age, for some types of amyloidosis aging is known as the main direct risk factor, and these types are typically diseases of elderly people. More than 10 different precursor proteins are known to cause age-associated amyloidosis; these proteins include amyloid β protein, α-synuclein, transthyretin, islet amyloid polypeptide, atrial natriuretic factor, and the newly discovered epidermal growth factor-containing fibulin-like extracellular matrix protein 1. Except for intracerebral amyloidoses, most age-related amyloidoses have been little studied. Indeed, in view of the increasing life expectancy in our societies, understanding how aging is involved in the process of amyloid fibril accumulation and the effects of amyloid deposits on the aging body is extremely important. In this review, we summarize current knowledge about the nature of amyloid precursor proteins, the prevalence, clinical manifestations, and pathogenesis of amyloidosis, and recent advances in our understanding of age-related amyloidoses outside the brain.     

Amyloid beta soluble forms and plasminogen activation system in Alzheimer’s disease: Consequences on extracellular maturation of brain‐derived neurotrophic factor and therapeutic implications

Soluble oligomeric forms of amyloid beta (Aβ) play an important role in causing the cognitive deficits in Alzheimer’s disease (AD) by targeting and disrupting synaptic pathways. Thus, the present research is directed toward identifying the neuronal pathways targeted by soluble forms and, accordingly, develops alternative therapeutic strategies. The neurotrophin brain‐derived neurotrophic factor (BDNF) is synthesized as a precursor (pro‐BDNF) which is cleaved extracellularly by plasmin to release the mature form. The conversion from pro‐BDNF to BDNF is an important process that regulates neuronal activity and memory processes. Plasmin‐dependent maturation of BDNF in the brain is regulated by plasminogen activator inhibitor‐1 (PAI‐1), the natural inhibitor of tissue‐type plasminogen activator (tPA). Therefore, tPA/PAI‐1 system represents an important regulator of extracellular BDNF/pro‐BDNF ratio. In this review, we summarize the data on the components of the plasminogen activation system and on BDNF in AD. Moreover, we will hypothesize a possible pathogenic mechanism caused by soluble Aβ forms based on the effects on tPA/PAI‐1 system and on the consequence of an altered conversion from pro‐BDNF to the mature BDNF in the brain of AD patients. Translation into clinic may include a better characterization of the disease stage and future direction on therapeutic targets.     

Plasmacytic cutaneous pathology: A review

We review the spectrum of cutaneous disorders associated with inflammatory and neoplastic plasmacytic pathology. Because plasma cells are derived from B‐lymphocytes our overview includes discussion of certain lymphoplasmacytic proliferations. It is structured along histopathological lines, addressing conditions characterized by (a) cutaneous plasma cell infiltrates, (b) deposits of plasma cell products or their derivatives in the skin and (c) miscellaneous, poorly understood cutaneous complications of plasmacytic disorders. Lesions arising primarily in the skin and those due to cutaneous involvement by multisystem disorders are addressed. The range includes a spectrum of tumefactive and circulatory manifestations. We highlight key clinical and pathological features of the different conditions and outline recent advances in our understanding of these entities. By emphasizing the dermatopathological characteristics of this spectrum of disorders we hope to hone the diagnostic accuracy of practitioners in the field.