Reduced mismatch negativity in mild cognitive impairment: associations with neuropsychological performance

Mild cognitive impairment (MCI) refers to a transitory state between healthy aging and dementia. Biomarkers are needed to facilitate early identification of MCI and predict progression to dementia. One potential neurophysiological biomarker, mismatch negativity (MMN), is an event-related potential reflecting fundamental, pre-attentive cognitive processes. MMN is reduced in normal aging and dementia and in neuropsychiatric samples and is associated with verbal memory deficits and poor executive functioning. This study aimed to investigate auditory MMN and its relationship to neuropsychological performance in MCI. Twenty-eight MCI participants and fourteen controls, aged ≥50 years, underwent neurophysiological and neuropsychological assessment, and completed questionnaires pertaining to disability. Relative to controls, the MCI group demonstrated reduced temporal MMN amplitude (p < 0.01). Reduced right temporal MMN was significantly associated with poorer verbal learning (r = 0.496; p < 0.01) and reduced left temporal MMN was significantly associated with increased self-reported disability (r = -0.419; p < 0.05). These results indicate that patients with MCI exhibit altered pre-attentive information processing, which in turn is associated with memory and psychosocial deficits. These findings overall suggest that MMN may be a viable neurophysiological biomarker of underlying disease in this 'at risk' group.     

Functional impairment in the diagnosis of mild cognitive impairment

The criterion on functional activity in the revised diagnostic criteria for mild cognitive impairment (MCI) seems to be conceptually and operationally problematic.We investigated the predictive validity for dementia of this criterion in 140 patients with MCI who participated in the baseline study of the Korean Longitudinal Study on Health and Aging and completed 18-month follow-up evaluation (mean duration of follow-up, 1.57±0.24 y). Annual conversion rates to dementia were compared between the patients who fulfilled the criterion on functional activity and those who did not. Annual conversion rates to dementia of the patients who fulfilled the criterion on functional activity was 4.76%, whereas that of the patients with MCI who did not was 33.07%, indicating that the criterion on functional activity was a significant negative predictor of dementia (odds ratio=0.12). Re-revision of the criterion on functional activity may be warranted to solve its conceptual and operational ambiguities.     

Functional deficits in patients with mild cognitive impairment: prediction of AD

OBJECTIVE: To evaluate the predictive utility of self-reported and informant-reported functional deficits in patients with mild cognitive impairment (MCI) for the follow-up diagnosis of probable AD. METHODS: The Pfeffer Functional Activities Questionnaire (FAQ) and Lawton Instrumental Activities of Daily Living (IADL) Scale were administered at baseline. Patients were followed at 6-month intervals, and matched normal control subjects (NC) were followed annually. RESULTS: Self-reported deficits were higher for patients with MCI than for NC. At baseline, self- and informant-reported functional deficits were significantly greater for patients who converted to AD on follow-up evaluation than for patients who did not convert, even after controlling for age, education, and modified Mini-Mental State Examination scores. While converters showed significantly more informant- than self-reported deficits at baseline, nonconverters showed the reverse pattern. Survival analyses further revealed that informant-reported deficits (but not self-reported deficits) and a discrepancy score indicating greater informant- than self-reported functional deficits significantly predicted the development of AD. The discrepancy index showed high specificity and sensitivity for progression to AD within 2 years. CONCLUSIONS: These findings indicate that in patients with MCI, the patient's lack of awareness of functional deficits identified by informants strongly predicts a future diagnosis of AD. If replicated, these findings suggest that clinicians evaluating MCI patients should obtain both self-reports and informant reports of functional deficits to help in prediction of long-term outcome.     

Increased functional connectivity within medial temporal lobe in mild cognitive impairment

Pathology at preclinical and prodromal stages of Alzheimer's disease (AD) may manifest itself as measurable functional change in neuronal networks earlier than detectable structural change. Functional connectivity as measured using resting‐state functional magnetic resonance imaging has emerged as a useful tool for studying disease effects on baseline states of neuronal networks. In this study, we use high resolution MRI to label subregions within the medial temporal lobe (MTL), a site of early pathology in AD, and report an increase in functional connectivity in amnestic mild cognitive impairment between entorhinal cortex and subregions of the MTL, with the strongest effect in the anterior hippocampus. However, our data also replicated the effects of decreased connectivity of the MTL to other nodes of the default mode network reported by other researchers. This dissociation of changes in functional connectivity within the MTL versus the MTL's connection with other neocortical structures can help enrich the characterization of early stages of disease progression in AD. © 2012 Wiley Periodicals, Inc.     

遗忘型轻度认知功能障碍的执行功能损害

目的探讨遗忘型轻度认知功能障碍患者执行功能变化的特点。方法依据Miyake的执行功能三因素模型(工作记忆、任务转换、反应抑制),使用E-prime软件对这三种执行功能核心成分编写检测任务:利用2-back任务和Keep-track任务检测工作记忆,Stop-signal任务和Stroop任务检测反应抑制,More-odd shift-ing任务检测任务转换能力。在34例遗忘型轻度认知功能障碍(amnestic mild cognitive impairement,aMCI)患者和31例正常老年人中进行这些任务的检测,比较两组间执行功能差异的特点。结果 aMCI组的执行功能比对照组显著降低(Wilks′λ=0.567,P﹤0.01)。除Stroop任务的数据两组间没有明显差异之外,aMCI组的2-back任务、Keep-track任务、Stop-signal任务、More-odd shifting任务的成绩均显著低于对照组(P<0.05),但这4种任务成绩下降的程度彼此间没有显著差异。结论aMCI阶段已经出现了执行功能的全面损害,三种执行功能核心成分均有受损。     

Resting-state global functional connectivity as a biomarker of cognitive reserve in mild cognitive impairment

Cognitive reserve (CR) shows protective effects in Alzheimer’s disease (AD) and reduces the risk of dementia. Despite the clinical significance of CR, a clinically useful diagnostic biomarker of brain changes underlying CR in AD is not available yet. Our aim was to develop a fully-automated approach applied to fMRI to produce a biomarker associated with CR in subjects at increased risk of AD. We computed resting-state global functional connectivity (GFC), i.e. the average connectivity strength, for each voxel within the cognitive control network, which may sustain CR due to its central role in higher cognitive function. In a training sample including 43 mild cognitive impairment (MCI) subjects and 24 healthy controls (HC), we found that MCI subjects with high CR (> median of years of education, CR+) showed increased frequency of high GFC values compared to MCI-CR- and HC. A summary index capturing such a surplus frequency of high GFC was computed (called GFC reserve (GFC-R) index). GFC-R discriminated MCI-CR+ vs. MCI-CR-, with the area under the ROC?=?0.84. Cross-validation in an independently recruited test sample of 23 MCI subjects showed that higher levels of the GFC-R index predicted higher years of education and an alternative questionnaire-based proxy of CR, controlled for memory performance, gray matter of the cognitive control network, white matter hyperintensities, age, and gender. In conclusion, the GFC-R index that captures GFC changes within the cognitive control network provides a biomarker candidate of functional brain changes of CR in patients at increased risk of AD.     

Intrinsic connectivity of hippocampal subfields in normal elderly and mild cognitive impairment patients

Hippocampal connectivity has been widely described but connectivity specificities of hippocampal subfields and their changes in early AD are poorly known. The aim of this study was to highlight hippocampal subfield networks in healthy elderly (HE) and their changes in amnestic patients with mild cognitive impairment (aMCI). Thirty‐six HE and 27 aMCI patients underwent resting‐state functional MRI scans. Specific intrinsic connectivity of bilateral CA1, SUB (subiculum), and CA2/3/4/DG was identified in HE (using seeds derived from manually delineation on high‐resolution scans) and compared between HE and aMCI. Compared to the other subfields, CA1 was more strongly connected to the amygdala and occipital regions, CA2/3/4/DG to the left anterior cingulate cortex, temporal, and occipital regions, and SUB to the angular, precuneus, putamen, posterior cingulate, and frontal regions. aMCI patients showed reduced connectivity within the SUB network (with frontal and posterior cingulate regions). Our study highlighted for the first time three specific and distinct hippocampal subfield functional networks in HE, and their alterations in aMCI. These findings are important to understand AD specificities in both cognitive deficits and lesion topography, given the role of functional connectivity in these processes. Hum Brain Mapp 38:4922–4932, 2017. © 2017 Wiley Periodicals, Inc.     

轻度认知功能障碍患者的执行功能和工作记忆研究

目的 了解轻度认知功能障碍(MO)患者的执行功能和工作记忆是否损害及工作记忆损害特点,探讨执行功能对MCI患者的日常生活活动能力(ADL)的影响.方法 运用神经心理学测试的方法对30例MCI患者进行执行功能、工作记忆及其他认知功能检查,同时进行ADL评定,另外选择30名健康老人作为对照组.结果 MCI组的执行功能和工作记忆成绩(分)显著低于对照组,其中数字颜色连线干扰(130.8±58.2)、数字颜色连线B(210.2±81.8)、词汇流畅性测试(8.9±5.4)、视觉客体工作记忆(0.73±0.12)和数字广度(3.4±0.9),除视觉空间工作记忆外,与对照组比较(52.0±13.5、121.0±33.4、16.4±5.4、0.85±9.18、4.2±1.1)差异均有统计学意义(t=7.108、5.159、-4.879、-4.351、-2.544,均P<0.01或P<0.05).用多元逐步回归方法分析执行功能对ADL的影响,结果 客体工作记忆、空间工作记忆和词汇流畅性与ADL的影响相关,而客体工作记忆与ADL的影响有显著相关性(β=-0.720,t=-3.571,P=0.001).结论 MCI患者具有明显的执行功能障碍和工作记忆损害,工作记忆与MCI患者的ADL有良好相关性,而且视觉客体工作记忆与MCI患者的ADL测查具有显著相关性,因此MCI患者的执行功能障碍可能是导致其ADL下降和客体工作记忆损害的主要因素.     

Motor function in subjects with mild cognitive impairment and early Alzheimer's disease

Basic mobility, balance, gait and dual-task performance were characterised in 140 consecutive subjects referred to a multidisciplinary university hospital in a geriatric setting for cognitive symptoms and possible dementia. After completion of an extensive diagnostic evaluation, subjects were classified into four diagnostic categories: no cognitive impairment, mild cognitive impairment, Alzheimer's disease (AD) and other dementia. Mean age was 57 +/- 9.2, 60 +/- 7.3, 68 +/- 9.9 and 64 +/- 10.5, respectively. Data on motor function, medication use and presence of white matter changes were evaluated and compared between the diagnostic groups. Motor function seems to be affected in very mild AD but not in mild cognitive impairment, as assessed with performance-based tests. AD subjects were slowed and had difficulties in dual-task performance requiring concurrently performing a cognitive task while walking.     

Functional magnetic resonance imaging of cholinergic modulation in mild cognitive impairment

PURPOSE OF REVIEW: Mild cognitive impairment often represents the earliest clinical phase of Alzheimer's disease and is thought to involve synaptic dysfunction. Functional neuroimaging methods may be sensitive to these early physiologic changes and may be useful in early detection, therapeutic monitoring, and prediction of treatment response and other clinical outcomes. This review will focus on functional magnetic resonance imaging and its use in measuring the effects of cholinergic modulation in mild cognitive impairment. RECENT FINDINGS: Functional magnetic resonance imaging has begun to be applied to measure changes in regional brain activation during cognitive task performance after pharmacologic manipulation. In mild cognitive impairment, recent reports have appeared demonstrating alterations in neocortical activation after acute and prolonged administration of acetylcholinesterase inhibitors. These functional changes may relate to both behavioral performance and measures of brain structure (e.g., hippocampal volume). SUMMARY: Pharmacologic functional magnetic resonance imaging is a rapidly emerging field, with applications in both basic human neuroscience and clinical psychiatry and neurology. Its use in mild cognitive impairment and Alzheimer's disease may provide novel insights into the cholinergic system, memory, and neurodegenerative disease.     

Medial temporal lobe function and structure in mild cognitive impairment

Functional magnetic resonance imaging (fMRI) was used to study memory-associated activation of medial temporal lobe (MTL) regions in 32 nondemented elderly individuals with mild cognitive impairment (MCI). Subjects performed a visual encoding task during fMRI scanning and were tested for recognition of stimuli afterward. MTL regions of interest were identified from each individual's structural MRI, and activation was quantified within each region. Greater extent of activation within the hippocampal formation and parahippocampal gyrus (PHG) was correlated with better memory performance. There was, however, a paradoxical relationship between extent of activation and clinical status at both baseline and follow-up evaluations. Subjects with greater clinical impairment, based on the Clinical Dementia Rating Sum of Boxes, recruited a larger extent of the right PHG during encoding, even after accounting for atrophy. Moreover, those who subsequently declined over the 2.5 years of clinical follow-up (44% of the subjects) activated a significantly greater extent of the right PHG during encoding, despite equivalent memory performance. We hypothesize that increased activation in MTL regions reflects a compensatory response to accumulating AD pathology and may serve as a marker for impending clinical decline.