Clinical and research value of the new diagnostic criteria for Alzheimer’s disease

概述

在阿尔茨海默氏病（Alzheimer’s disease, AD）的诊断中采用生物标志物已日益得到重视，但在临床实践中使用生物标志物的可行性和价值仍然是有限的。然而，AD临床和制药研究中生物标志物的使用也许可以证明对明确AD的病理基础是非常有用的，并有助于提高在有效预防和治疗措施下的早期识别。此外，新诊断标准的广泛采用将提高不同研究结果之间的可比性，并为使用meta分析方法合并和比较不同研究的结果创造了可能性——这种分析能够明确回答关于AD的病因、病程、预防和治疗等基本问题。

中文全文

本文全文中文版从2015年6月6日起在http://dx.doi.org/10.11919/j.issn.1002-0829.215046可供免费阅览下载As discussed in the Forum article by Yang and Xiao, [1] in recent years there has been an increasing emphasis on the role of biomarkers in the diagnosis of Alzheimer’s disease (AD). Nonetheless, there are several potential serious problems in the clinical application of biomarkerbased diagnostic criteria for AD: a) The reliability of the biomarkers is not proven. Currently, there is a lack of consensus on the cutoff points that provide satisfactory sensitivity and specificity of the proposed biomarkers that would best distinguish ‘normal’ from ‘abnormal’. More clinical studies are needed to unify and standardize the proposed cutoffs points. For instance, amyloidbeta (Aβ) accumulation is also detected in healthy individuals, [2] and the specificity of identifying AD using cerebrospinal fluid (CSF) Aβ₄₂ and CSF tau varies from 49% to 77%. [3] At present the diagnosis of AD cannot rely solely on such biomarkers. b) The feasibility of assessing biomarkers is limited in clinical settings. The lack of an ideal tracer for PET and differences in Aβ and tau standards at different research institutes limits the broad application of these techniques. More importantly, the use of the tests for biomarkers is limited to locations that have the advanced (and expensive) equipment needed to make the assessments and the highly trained technicians who can operate and maintain the equipment and interpret the results. In low- or middle-income countries, these facilities are only available in prestigious health centers in large urban areas. Additional limitations may occur in countries where cultural factors c) There are ethical concerns about the early diagnosis of AD.The new diagnostic criteria stress the importance of early detection and propose the concept of a prodromal phase of AD. Some scholars suggest that the early detection of AD using biomarkers is little different from identifying carcinoma in situ (CIS) or using laboratory tests to identify prodromal phases of type-II diabetes, hypertension, renal insufficiency, and osteoporosis. However, the situation with AD is different because there is, as yet, little evidence that early detection and treatment of high-risk individuals (i.e., individuals with mild cognitive impairment) has any beneficial effects. [4,5] Furthermore, the psychological burden that is experienced by the individual and the individual’s family when an early diagnosis is made by a treating clinician can be as great as that caused by the disease itself. [6] Thus, there are serious ethical issues related to the early diagnosis of AD that are more prominent than those related to the early diagnosis of other conditions for which effective treatments are already available. d) The theoretical foundation of the new diagnostic criteria is inadequate.The new diagnostic criteria are completely based on theories about disturbed metabolism of Aβ and the resultant accumulation of Aβ. But this is only one of many etiological mechanisms that result in AD, so the markers only identify a subset of cases. Moreover, the proposed biomarkers are not pathognomonic, some individuals with these markers never develop AD. Despite these problems, it is undeniable that the emphasis on biomarkers in the new diagnostic criteria is an improvement. Studies on biomarkers have demonstrated that the conventional symptomologybased diagnostic criteria of AD can delay treatment because clinical symptoms greatly lag behind the actual onset of the disease. This delayed diagnosis delays both the clinical treatment of affected individuals and the development of new medications of other interventions to prevent or treat AD. Despite the uncertainty of their use in clinical practice, adopting biomarkers in clinical research and pharmaceutical studies can help distinguish AD from other types of dementia, advance our understanding of the pathology of AD, promote the initiation of interventions and treatments earlier in the course of the condition, improve the quality of the evaluation of effectiveness, and, thus, help in the development of new drugs and other treatments. A search on Web of Science found that many researchers are already publishing results based on these new diagnostic criteria. As of 5 April 2015 there have been 1059 articles published using the NINCDSADRDA criteria, 864 articles published using the NIAAA criteria, and 21 articles published using the IWG-2 criteria. The widespread use of these new diagnostic criteria in research studies can help homogenize the selection of samples and, thus, greatly improve the comparability of the studies. It would then be feasible to combine such studies in meta-analysis with large pooled samples, the type of comprehensive analyses that will be needed to provide clear answers to many of the perplexing issues that need to be resolved before it will be possible to identify effective interventions for this disabling condition. Additional work in the future will be needed to identify a subset of relatively easy to identity biomarkers that can be used in routine clinical care, particularly in low-resource settings in low- and middleincome countries.     

阿尔茨海默病与血管性痴呆患者精神行为症状和认知功能损害的比较

目的:探讨阿尔茨海默病(AD)和血管性痴呆(VD)患者精神行为症状和认知功能损害特点。方法:分析53例AD患者(AD组)及49例VD患者(VD组)近1个月精神行为症状及发生率;采用简明精神状态检查(MMSE)、世界卫生组织-加利福尼亚大学听觉词语学习测验(WHO-UCLA AVLT)和画钟测验(CDT)评估两组患者的认知功能。结果:AD组攻击行为、行为紊乱发生率明显高于VD组,抑郁发生率明显低于VD组(P均0.05);AD组MMSE中记忆、言语能力评分显著低于VD组,注意力评分显著高于VD组(P均0.05);AD组WHO-UCLA AVLT中延时记忆、长时记忆评分显著低于VD组(P均0.05);两组间CDT评分差异无统计学意义。结论:AD患者较VD患者有更多的攻击行为及行为紊乱,认知功能损害以记忆、言语能力下降更重;VD患者较多出现抑郁症状,注意力损害更明显。     

Cognitive profiles in Mild Cognitive Impairment (MCI) patients associated with Parkinson's disease and cognitive disorders

Background:

Mild cognitive impairment (MCI) is rapidly becoming one of the most common clinical manifestations affecting the elderly and represents an heterogeneous clinical syndrome that can be ascribed to different etiologies; the construct of MCI in Parkinson''s disease (PD) (MCI-PD) is more recent but the range of deficits is still variable. Early recognition and accurate classification of MCI-PD could offer opportunities for novel therapeutic interventions to improve the natural pathologic course.

Objective:

To investigate the clinical phenotype of amnestic mild cognitive impairment (aMCI) and in patients with PD and MCI (MCI-PD).

Materials and Methods:

Seventy-three patients with aMCI and in 38 patients with MCI-PD were enrolled. They all underwent Mini–mental State Examination (MMSE), the Rey auditory-verbal learning test and the immediate visual memory (IVM) item of the Mental Deterioration Battery, the Rey auditory-verbal learning test included the Rey-immediate (Rey-I), and the delayed recall of the word list (Rey test deferred, Rey-D). The Geriatric Depression Scale (GDS) was used for mood assessment.

Results:

The results of the Rey-I and Rey-D and of the IVM item showed statistically significant differences between the aMCI and the MCI-PD group. The mean Rey-I and Rey-D score was significantly lower as well as the IVM score was higher in patients with aMCI than in those with MCI-PD, aMCI patients showed greater impairment in long-term memory, whereas more aMCI than MCI-PD patients had preserved attention, computation, praxis, and conceptualization.

Conclusions:

Our findings demonstrate that the cognitive deficit profile is specific for each of the two disorders: Memory impairment was a typical feature in aMCI patients while MCI-PD patients suffered from executive functions and visuospatial attention deficits.     

Human neural stem cells improve cognition and promote synaptic growth in two complementary transgenic models of Alzheimer's disease and neuronal loss

Alzheimer's disease (AD) is the most prevalent age‐related neurodegenerative disorder, affecting over 35 million people worldwide. Pathologically, AD is characterized by the progressive accumulation of β‐amyloid (Aβ) plaques and neurofibrillary tangles within the brain. Together, these pathologies lead to marked neuronal and synaptic loss and corresponding impairments in cognition. Current treatments, and recent clinical trials, have failed to modify the clinical course of AD; thus, the development of novel and innovative therapies is urgently needed. Over the last decade, the potential use of stem cells to treat cognitive impairment has received growing attention. Specifically, neural stem cell transplantation as a treatment for AD offers a novel approach with tremendous therapeutic potential. We previously reported that intrahippocampal transplantation of murine neural stem cells (mNSCs) can enhance synaptogenesis and improve cognition in 3xTg‐AD mice and the CaM/Tet‐DT_A model of hippocampal neuronal loss. These promising findings prompted us to examine a human neural stem cell population, HuCNS‐SC, which has already been clinically tested for other neurodegenerative disorders. In this study, we provide the first evidence that transplantation of research grade HuCNS‐SCs can improve cognition in two complementary models of neurodegeneration. We also demonstrate that HuCNS‐SC cells can migrate and differentiate into immature neurons and glia and significantly increase synaptic and growth‐associated markers in both 3xTg‐AD and CaM/Tet‐DT_A mice. Interestingly, improvements in aged 3xTg‐AD mice were not associated with altered Aβ or tau pathology. Rather, our findings suggest that human NSC transplantation improves cognition by enhancing endogenous synaptogenesis. Taken together, our data provide the first preclinical evidence that human NSC transplantation could be a safe and effective therapeutic approach for treating AD. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Evidence of neurodegeneration in obstructive sleep apnea: Relationship between obstructive sleep apnea and cognitive dysfunction in the elderly

The incidence of dementia and obstructive sleep apnea (OSA) increases with age. Late‐onset Alzheimer's disease (AD) is an irreversible neurodegenerative disease of the elderly characterized by amyloid β (Aβ) plaques and neurofibrillary tangles. The disease involves widespread synaptic loss in the neocortex and the hippocampus. Rodent and clinical studies suggest that OSA impairs the structural integrity of several brain regions, including the medial temporal lobe. Indeed, hypoxia, hypertension, hypoperfusion, endothelial dysfunction, inflammation, and oxidative stress noted in OSA patients also occur in AD patients. This Review highlights pathological commonality, showing that OSA upregulates Aβ, tau hyperphosphorylation, and synaptic dysfunction. Indeed, OSA and hypertension trigger hypoperfusion and hypometabolism of brain regions, including cortex and hippocampus. Several studies show that hypertension‐driven brain damage and pathogenic mechanisms lead to an Aβ increase. The pathophysiological mechanism by which OSA enhances hypertension may be linked to sympathoexcitation, oxidative stress, and endothelial dysfunction. Strong pathophysiological similarities that exist between OSA and AD are underscored here. For example, the hippocampus is negatively impacted in both OSA and AD. OSA promotes hippocampal atrophy, which is associated with memory impairment. Cognitive impairment, even in the absence of manifest dementia, is an important independent predictor of mortality. However, several pathophysiological mechanisms in OSA are reversible with appropriate therapy. OSA, therefore, is a modifiable risk factor of cognitive dysfunction, and treating OSA prior to mild cognitive impairment may be an effective prevention strategy to reduce risk for cognitive decline and AD in middle‐aged persons and the elderly. © 2015 Wiley Periodicals, Inc.     

Executive function deficits and glutamatergic protein alterations in a progressive 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson's disease

Changes in executive function are at the root of most cognitive problems associated with Parkinson's disease. Because dopaminergic treatment does not necessarily alleviate deficits in executive function, it has been hypothesized that dysfunction of neurotransmitters/systems other than dopamine (DA) may be associated with this decrease in cognitive function. We have reported decreases in motor function and dopaminergic/glutamatergic biomarkers in a progressive 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) Parkinson's mouse model. Assessment of executive function and dopaminergic/glutamatergic biomarkers within the limbic circuit has not previously been explored in our model. Our results show progressive behavioral decline in a cued response task (a rodent model for frontal cortex cognitive function) with increasing weekly doses of MPTP. Although within the dorsolateral (DL) striatum mice that had been given MPTP showed a 63% and 83% loss of tyrosine hydroxylase and dopamine transporter expression, respectively, there were no changes in the nucleus accumbens or medial prefrontal cortex (mPFC). Furthermore, dopamine‐1 receptor and vesicular glutamate transporter (VGLUT)?1 expression increased in the mPFC following DA loss. There were significant MPTP‐induced decreases and increases in VGLUT‐1 and VGLUT‐2 expression, respectively, within the DL striatum. We propose that the behavioral decline following MPTP treatment may be associated with a change not only in cortical–cortical (VGLUT‐1) glutamate function but also in striatal DA and glutamate (VGLUT‐1/VGLUT‐2) input. © 2015 Wiley Periodicals, Inc.     

An activated sympathetic nervous system affects white adipocyte differentiation and lipolysis in a rat model of Parkinson's disease

Weight loss is an important nonmotor symptom associated with Parkinson's disease (PD). However, the cellular factors responsible for PD‐induced weight loss remain unclear. Because the sympathetic nervous system plays an important role in lipid metabolism and fat cell differentiation, this study investigates whether PD‐induced changes to this system are associated with weight loss in a rat model of PD. Body weight and food intake were measured in control and PD‐model rats. After 10 weeks, retroperitoneal white adipose tissues (RWAT) were removed and weighed. Markers of the sympathetic nervous system were measured in the brainstem dorsal medulla and RWAT. Free fat acids (FFA), triglycerides (TG), adipocyte differentiation‐related genes, and lipolysis‐related molecules in the RWAT and serum were analyzed. Differences in body weight and food intake were insignificant in PD‐model rats and control rats; however, relative RWAT weight and adipocyte surface area were significantly reduced in the PD group. Changes in markers of the sympathetic nervous system were observed in the brainstem dorsal medulla and RWAT of PD rats. Decreased mRNA expression levels of genes involved in adipocyte differentiation, decreased TG levels in RWAT, increased FFA in RWAT, and increased lipolysis‐related molecules in RWAT and serum FFA were observed in PD rats. This study demonstrates that degenerated dopaminergic neurons in the nigrostriatal system correlate with increases in sympathetic nervous system function, resulting in lipolysis and inhibition of fat cell differentiation. These factors ultimately result in the decrease of RWAT in PD‐model rats. © 2014 Wiley Periodicals, Inc.     

Mass spectrometric identification of citrullination sites and immunohistochemical detection of citrullinated glial fibrillary acidic protein in Alzheimer's disease brains

Peptidylarginine deiminases (PADs) are posttranslational modification enzymes that convert protein arginine to citrulline residues in a calcium ion‐dependent manner. Previously, we reported the abnormal accumulation of citrullinated proteins and the increase in the amount of PAD2 in hippocampi from Alzheimer's disease (AD) patients. Moreover, glial fibrillary acidic protein (GFAP), an astrocyte‐specific marker protein, and vimentin were identified as citrullinated proteins by using two‐dimensional gel electrophoresis and MALDI‐TOF mass spectrometry. To clarify the substrate specificity of PADs against GFAP, we prepared recombinant human (rh)PAD1, rhPAD2, rhPAD3, rhPAD4, and rhGFAP. After incubation of rhGFAP with rhPAD1, rhPAD2, rhPAD3, and rhPAD4, citrullinated (cit‐)rhGFAP was detected by Western blotting. The citrullination of rhGFAP by rhPAD2 was unique, specific, and time dependent; additionally, rhPAD1 slightly citrullinated rhGFAP. We then generated eight anti‐cit‐rhGFAP monoclonal antibodies, CTGF‐125, ?128, ?129, ?1212, ?1213, ?1221, ?122R, and ?1224R, which reacted specifically with cit‐rhGFAP. Two of those eight monoclonal antibodies, CTGF‐122R and ?1224R, reacted with both cit‐rhGFAP and rhGFAP in Western blots. By using the CTGF‐1221 antibody and a tandem mass spectrometer, we identified the two independent citrullination sites (R270Cit and R416Cit) of cit‐rhGFAP. Immunohistochemical analysis with CTGF‐1221 antibody revealed cit‐GFAP staining in the hippocampus of AD brain, and the cit‐GFAP‐positive cells appeared to be astrocyte‐like cells. These collective results strongly suggest that PAD2 is responsible for the citrullination of GFAP in the progression of AD and that the monoclonal antibody CTGF‐1221, reacting with cit‐GFAP at R270Cit and R416Cit, is useful for immunohistochemical investigation of AD brains. © 2015 Wiley Periodicals, Inc.     

Evidence for early and progressive ultrasonic vocalization and oromotor deficits in a PINK1 gene knockout rat model of Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disease that leads to a wide range of motor and nonmotor deficits. Specifically, voice and swallow deficits manifest early, are devastating to quality of life, and are difficult to treat with standard medical therapies. The pathological hallmarks of PD include accumulation of the presynaptic protein α‐synuclein (αSyn) as well as degeneration of substantia nigra dopaminergic neurons. However, there is no clear understanding of how or when this pathology contributes to voice and swallow dysfunction in PD. The present study evaluates the effect of loss of function of the phosphatase and tensin homolog‐induced putative kinase 1 gene in rats (PINK1^–/–), a model of autosomal recessive PD in humans, on vocalization, oromotor and limb function, and neurodegenerative pathologies. Behavioral measures include ultrasonic vocalizations, tongue force, biting, and gross motor performance that are assayed at 2, 4, 6, and 8 months of age. Aggregated αSyn and tyrosine hydroxylase immunoreactivity (TH‐ir) were measured at 8 months. We show that, compared with wild‐type controls, PINK1^–/– rats develop 1) early and progressive vocalization and oromotor deficits, 2) reduced TH‐ir in the locus coeruleus that correlates with vocal loudness and tongue force, and 3) αSyn neuropathology in brain regions important for cranial sensorimotor control. This novel approach of characterizing a PINK1^–/– genetic model of PD provides the foundational work required to define behavioral biomarkers for the development of disease‐modifying therapeutics for PD patients. © 2015 Wiley Periodicals, Inc.