Regional white matter hyperintensities in normal aging, single domain amnestic mild cognitive impairment, and mild Alzheimer’s disease

Few studies have examined white matter hyperintensities (WMH) along the cognitive continuum between single-domain amnestic mild cognitive impairment (sd-aMCI) and Alzheimer’s disease (AD). The aims of our study were to explore relationships between the extent and location of WMH and disease severity along the cognitive continuum and to determine whether differences in the distribution of WMH could be predictive of specific patterns of cognitive impairment. We compared cognitive function, vascular risk factors, and regional (frontal lobe, parieto-occipital [PO] lobe, temporal lobe, periventricular [PV] white matter and deep white matter) WMH volume in 37 patients with mild AD, 23 patients with sd-aMCI, and 24 age-matched and education-matched normal controls. A quantitative volumetric method was applied to measure WMH burden. Total and regional WMH burdens, except for those in the temporal lobe, were significantly correlated with age (p < 0.01). We found a trend toward increasing WMH volume with disease severity, higher in AD than in sd-aMCI and lowest in the controls. Total WMH volume was associated with the global cognitive test score. In multiple linear regression analysis, PV WMH volume, but not deep WMH volume, strongly predicted performances on the Controlled Oral Word Association test and the Color Word Stroop test after adjusting for important demographic variables. Only PO WMH volume was a significant predictor of a cognitive test score when frontal and temporal WMH volumes were simultaneously entered into the regression model. The extent and distribution of WMH, especially in the PV and PO regions, were associated with disease severity and reduced cognition.     

Macrophage migration inhibitory factor in mild cognitive impairment and Alzheimer’s disease

Inflammatory processes may substantially contribute to the cerebral pathology in Alzheimer’s disease (AD) and accelerate the disease progression. The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine which promotes the production of several inflammatory mediators such as TNF-α, IL-6 and IFN-γ, and plays a central regulatory role in the pathogenesis of several inflammatory and autoimmune diseases. There is now first evidence that MIF may be involved in the neuroinflammation in AD. To determine whether MIF production is up-regulated early in the course of AD, we compared the levels of MIF assessed by ELISA in the cerebrospinal fluid (CSF) of 31 patients with AD, 28 patients with amnestic mild cognitive impairment (MCI), and 19 subjects without cognitive deficits. Additionally, we measured the CSF concentrations of the inflammatory mediators TNF-α, IL-6 and IFN-γ, which are thought to be both up-regulated by MIF and involved in the pathophysiology of AD. CSF MIF concentrations were significantly increased in AD (p = 0.003) and MCI patients (p < 0.001) compared to controls. The levels of TNF-α, IL-6 and IFN-γ did not differ significantly between the groups. There was a correlation only between the concentrations of MIF and of TNF-α in the AD group (r = 0.407; p = 0.023). These results demonstrate increased MIF production in AD and MCI suggesting that MIF may be involved in the occurring neuroinflammatory process at a clinical pre-dementia disease stage.     

The cognitive and neural expression of semantic memory impairment in mild cognitive impairment and early Alzheimer's disease

Semantic deficits in Alzheimer's disease have been widely documented, but little is known about the integrity of semantic memory in the prodromal stage of the illness. The aims of the present study were to: (i) investigate naming abilities and semantic memory in amnestic mild cognitive impairment (aMCI), early Alzheimer's disease (AD) compared to healthy older subjects; (ii) investigate the association between naming and semantic knowledge in aMCI and AD; (iii) examine if the semantic impairment was present in different modalities; and (iv) study the relationship between semantic performance and grey matter volume using voxel-based morphometry. Results indicate that both naming and semantic knowledge of objects and famous people were impaired in aMCI and early AD groups, when compared to healthy age- and education-matched controls. Item-by-item analyses showed that anomia in aMCI and early AD was significantly associated with underlying semantic knowledge of famous people but not with semantic knowledge of objects. Moreover, semantic knowledge of the same concepts was impaired in both the visual and the verbal modalities. Finally, voxel-based morphometry analyses revealed that semantic impairment in aMCI and AD was associated with cortical atrophy in the anterior temporal lobe (ATL) region as well as in the inferior prefrontal cortex (IPC), some of the key regions of the semantic cognition network. These findings suggest that the semantic impairment in aMCI may result from a breakdown of semantic knowledge of famous people and objects, combined with difficulties in the selection, manipulation and retrieval of this knowledge.     

Increased platelet GSK3B activity in patients with mild cognitive impairment and Alzheimer’s disease

The disruption of glycogen synthase kinase 3-beta (GSK3B) homeostasis has implications in the pathophysiology of neuropsychiatric disorders, namely Alzheimer’s disease (AD). GSK3B activity is increased within the AD brain, favoring the hyperphosphorylation of microtubule-associated protein Tau and the formation of neurofibrillary tangles. Such abnormality has also been detected in leukocytes of patients with cognitive disorders. The aim of the present study was to determine the expression of total and phosphorylated GSK3B at protein level in platelets of older adults with varying degrees of cognitive impairment, and to compare GSK3B activity in patients with AD, mild cognitive impairment (MCI) and healthy controls. Sixty-nine older adults were included (24 patients with mild to moderate AD, 22 patients with amnestic MCI and 23 elderly controls). The expression of platelet GSK3B (total- and Ser-9 phosphorylated GSK3B) was determined by Western blot. GSK3B activity was indirectly assessed by means of the proportion between phospho-GSK3B to total GSK3B (GSK3B ratio), the former representing the inactive form of the enzyme. Ser-9 phosphorylated GSK3B was significantly reduced in patients with MCI and AD as compared to controls (p = 0.04). Platelet GSK3B ratio was significantly decreased in patients with MCI and AD (p = 0.04), and positively correlated with scores on memory tests (r = 0.298, p = 0.01). In conclusion, we corroborate previous evidence of increased GSK activity in peripheral tissues of patients with MCI and AD, and further propose that platelet GSK may be an alternative peripheral biomarker of this abnormality, provided samples are adequately handled in order to preclude platelet activation.     

Amnestic mild cognitive impairment in Parkinson's disease: A brain perfusion SPECT study

The purpose of this study was to investigate cortical dysfunction in Parkinson's disease (PD) patients with amnestic deficit (PD‐MCI). Perfusion single photon emission computed tomography was performed in 15 PD‐MCI patients and compared (statistical parametric mapping [SPM2]) with three groups, i.e., healthy subjects (CTR), cognitively intact PD patients (PD), and common amnestic MCI patients (aMCI). Age, depression, and UPDRS‐III scores were considered as confounding variables. PD‐MCI group (P < 0.05, false discovery rate–corrected for multiple comparisons) showed relative hypoperfusion in bilateral posterior parietal lobe and in right occipital lobe in comparison to CTR. As compared to aMCI, MCI‐PD demonstrated hypoperfusion in bilateral posterior parietal and occipital areas, mainly right cuneus and angular gyrus, and left precuneus and middle occipital gyrus. With a less conservative threshold (uncorrected P < 0.01), MCI‐PD showed hypoperfusion in a left parietal region, mainly including precuneus and inferior parietal lobule, and in a right temporal‐parietal‐occipital region, including middle occipital and superior temporal gyri, and cuneus‐precuneus, as compared to PD. aMCI versus PD‐MCI showed hypoperfusion in bilateral medial temporal lobe, anterior cingulate, and left orbitofrontal cortex. PD‐MCI patients with amnestic deficit showed cortical dysfunction in bilateral posterior parietal and occipital lobes, a pattern that can be especially recognized versus both controls and common aMCI patients, and to a lesser extent versus cognitively intact PD. The relevance of this pattern in predicting dementia should be evaluated in longitudinal studies. © 2008 Movement Disorder Society     

Perceptual and response interference in Alzheimer’s disease and mild cognitive impairment

Objectives

The ability to resolve conflicts is indispensable to the function of daily life and decreases with cognitive decline. We hypothesized that subjects with different levels of cognitive impairment exhibit different conflict resolution performances and may be susceptible to interference effects at different stages.

Methods

Sixteen normal controls (NC), 15 mild cognitive impairment (MCI) and seven Alzheimer’s disease (AD) patients were recruited to perform in a modified Eriksen flanker task.

Results

We observed that the AD and MCI patients exhibited smaller accuracy rate and longer response time compared to NC subjects. Longer N2 and P300 latencies were observed in the AD group. Furthermore, the MCI group showed a longer latency than the NC group in the P300 latency. The magnitude of the perceptual and response interference effects was larger in the AD group than the other groups, and the MCI group significantly differed from the NC group at the perceptual level.

Conclusion

The ability to resolve conflict decreased with impaired cognition and the perceptual and response interference effects may be useful in distinguishing MCI and AD.

Significance

The perceptual or response interference effect may potentially be employed as a useful non-invasive probe for the clinical diagnosis of MCI and AD.     

CERAD test performances in amnestic mild cognitive impairment and Alzheimer's disease

OBJECTIVES: The aim of the study was to examine the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test performances cross-sectionally in patients suffering from amnestic mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Moreover, we wanted to determine the sensitivity to amnestic MCI and mild AD, as well as the specificity of different CERAD subtests in our study groups. MATERIAL AND METHODS: Fifteen healthy elderly individuals, 15 amnestic MCI patients and 15 probable AD patients suffering from mild dementia were tested with the CERAD neurocognitive dementia screening test. RESULTS: Significant differences were found in all CERAD tests except Constructional praxis (copy) and Clock drawing between the controls and the AD group. The MCI group was differentiated from the controls only in the Wordlist learning test. In the language tests the sensitivity to MCI and AD was quite low and the specificity very high. In the savings scores the sensitivity to AD was high, but the specificity rather low. The Wordlist recognition test screened no false positives using the current cut-off score and the sensitivity to AD was 0.6, but only one MCI patient was detected using the current cut-off score. Raising the cut-off score also raised the sensitivity to MCI without dramatic loss of specificity. Cut-off scores for the Wordlist learning test and Wordlist delayed recall, which have been found to differentiate normal aging from dementia, are lacking in the Finnish CERAD. The current data indicates that the Wordlist learning test might be relatively sensitive to MCI. CONCLUSIONS: The results indicate that the Finnish CERAD test battery with its current cut-off scores has low sensitivity to MCI, and using it as a sole cognitive screening instrument for MCI and preclinical dementia might result in false negatives.     

Differences in grey and white matter atrophy in amnestic mild cognitive impairment and mild Alzheimer's disease

Background:  Grey matter (GM) atrophy has been demonstrated in amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD), but the role of white matter (WM) atrophy has not been well characterized. Despite these findings, the validity of aMCI concept as prodromal AD has been questioned.
Methods:  We performed brain MRI with voxel-based morphometry analysis in 48 subjects, aiming to evaluate the patterns of GM and WM atrophy amongst mild AD, aMCI and age-matched normal controls.
Results:  Amnestic mild cognitive impairment GM atrophy was similarly distributed but less intense than that of mild AD group, mainly in thalami and parahippocampal gyri. There were no difference between aMCI and controls concerning WM atrophy. In the mild AD group, we found WM atrophy in periventricular areas, corpus callosum and WM adjacent to associative cortices.
Discussion:  We demonstrated that aMCI might be considered a valid concept to detect very early AD pathology, since we found a close proximity in the pattern of atrophy. Also, we showed the involvement of WM in mild AD, but not in aMCI, suggesting a combination of Wallerian degeneration and microvascular ischaemic disease as a plausible additional pathological mechanism for the discrimination between MCI and AD.     

Alzheimer's disease and mild cognitive impairment deteriorate fine movement control

Sensory-motor dysfunctions are often associated with Alzheimer’s disease (AD) or mild cognitive impairment (MCI). This study suggests that deterioration in fine motor control and coordination characterizes sensory-motor deficiencies of AD and MCI. Nine patients with a clinical diagnosis of probable AD, 9 amnestic MCI subjects and 10 cognitively normal controls performed four types of handwriting movement on a digitizer. Movement time and smoothness were analyzed between the groups and across the movement patterns. Kinematic profiles were also compared among the groups. AD and MCI patients demonstrated slower, less smooth, less coordinated, and less consistent handwriting movements than their healthy counterparts. The theoretical relevance and practical implications of fine motor tasks, such as these movements involved in handwriting, are discussed relative to the deteriorated sensory-motor system of AD and MCI patients.     

Identifying functional imaging markers of mild cognitive impairment in early Alzheimer’s and Parkinson’s disease using multivariate analysis

Functional neuroimaging, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), provides a valuable technique for detecting regional changes in brain metabolic activity and blood flow associated with mild cognitive impairment (MCI) and dementia. Multivariate analysis techniques have recently received increasing attention. The results of multivariate analysis can be more easily interpreted as a signature of neuronal networks, which lend themselves to prospective application of results from the analysis of one dataset to entirely new datasets. They are well placed to provide information about mean differences and correlations with behavior with potentially greater statistical power and better reproducibility. This article will focus on investigating the baseline and progression of MCI using functional brain imaging techniques and multivariate analysis in order to understand the genesis and natural history of cognitive impairment in Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively.     

Defining mild cognitive impairment in Parkinson's disease

Our purpose was to characterize a state of mild cognitive impairment (MCI) in Parkinson's disease (PD) (PD‐MCI) that would be analogous to the MCI that is posited as a precursor of Alzheimer's disease (AD). We categorized 86 PD subjects in a brain bank population as either cognitively normal (PD‐CogNL), PD‐MCI using criteria that included a 1.5 standard deviation or greater deficit upon neuropsychological testing consistently across at least one cognitive domain without dementia, and PD dementia (PD‐D) using DSM‐IV criteria. Twenty‐one percent of our PD sample met criteria for PD‐MCI, 62% were PD‐CogNL, and 17% had PD‐D. The mean duration of PD and MMSE scores of the PD‐MCI group were intermediate and significantly different from both PD‐CogNL and PD‐D. The cognitive domain most frequently abnormal in PD‐MCI was frontal/executive dysfunction followed by amnestic deficit. Single domain PD‐MCI was more common than PD‐MCI involving multiple domains. We conclude that a stage of clinical cognitive impairment in PD exists between PD‐CogNL and PD‐D, and it may be defined by applying criteria similar to the MCI that is posited as a precursor of AD. Defining PD‐MCI offers an opportunity for further study of cognitive impairment in PD and targets for earlier therapeutic intervention. © 2007 Movement Disorder Society     

Semantic knowledge in mild cognitive impairment and mild Alzheimer's disease

The aim of this study was to investigate memory in patients with mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Ten patients with MCI, 11 with AD and a group of age and education matched healthy control participants were assessed on a comprehensive battery of semantic memory tests, including traditional semantic memory measures and a non-verbal test of knowledge of object use. The MCI group was impaired on tests of category fluency and all three conditions of an object knowledge test (matching to recipient, function and action), plus a difficult object-naming test. The mild AD group showed additional impairments on traditional measures of semantic memory, including naming high frequency items, comprehension and semantic association. Together these findings suggest that semantic memory impairments occur early in the course of AD, more specifically in patients with "amnesic" MCI, and provide further evidence that impaired category fluency reflects semantic breakdown.     

Characterizing mild cognitive impairment in Parkinson's disease

There is growing interest in identifying Parkinson's disease (PD) patients with mild cognitive impairment (PD‐MCI), but widely disparate criteria have been used. We assessed 143 PD patients and 50 matched controls on 20 measures across 4 cognitive domains (executive function, attention and working memory, learning and memory, visuoperception). Twenty‐four patients met criteria for dementia (PD‐D); nondementia patients were classified as either with normal cognition or MCI for 12 neuropsychological criteria. We compared the influence of these criteria on the distribution of global cognitive performance in the resulting PD‐MCI groups relative to the control and PD‐D groups. Different criteria produced substantial variation in the proportion of PD‐MCI cases identified. Fourteen percent PD‐MCI was found when using 2 scores in 1 domain at 2 standard deviations (SD) below normative scores, with no controls identified as MCI, through to 89% PD‐MCI with 1 score in 1 domain at 1 SD below normative scores, when 70% of controls were identified as MCI. The balance of cases with impaired cognition but not those with generally intact cognition was better served by using criteria that required 2 specific deficit scores or deficits across 2 domains. As comparisons with external normative data may have greater applicability across centers, we suggest that 2 scores at ?1.5 SD within any single domain (30% PD‐MCI) or 1 score at ?1.5 SD in each of 2 domains (37% PD‐MCI) provide suitable criteria to minimize the inclusion of cognitively well patients. Clinical dementia rating did not improve the relative identification of cognitively impaired and unimpaired nondementia PD patients. © 2011 Movement Disorder Society     

β淀粉样蛋白对阿尔茨海默病转基因果蝇认知功能的影响

目的 探讨Aβ40、Aβ42、Aβ42Arc对阿尔茨海默病(AD)转基因果蝇认知功能的影响.方法 分别建立Aβ40、Aβ42、Aβ42Arc转基因AD果蝇模型.根据实验要求将果蝇分为4组,分别是野生果蝇对照组、Aβ40组、Aβ42组、Aβ42 Arc组.在整体动物水平上进行果蝇行为学研究,分别检测各组果蝇的嗅觉短期记忆能力、攀爬能力和平均寿命.结果 在巴甫洛夫嗅觉相关短期记忆测试、攀爬能力试验、平均寿命测试中,与对照组相比,3组转基因果蝇的嗅觉记忆能力、攀爬能力、平均寿命均明显降低.结论 Aβ的毒性作用会导致AD转基因果蝇认知功能下降.     

Biomarkers for dementia and mild cognitive impairment in Parkinson's disease

Cognitive decline is one of the most frequent and disabling nonmotor features of Parkinson's disease. Around 30% of patients with Parkinson's disease experience mild cognitive impairment, a well‐established risk factor for the development of dementia. However, mild cognitive impairment in patients with Parkinson's disease is a heterogeneous entity that involves different types and extents of cognitive deficits. Because it is not currently known which type of mild cognitive impairment confers a higher risk of progression to dementia, it would be useful to define biomarkers that could identify these patients to better study disease progression and possible interventions. In this sense, the identification among patients with Parkinson's disease and mild cognitive impairment of biomarkers associated with dementia would allow the early detection of this process. This review summarizes studies from the past 25 years that have assessed the potential biomarkers of dementia and mild cognitive impairment in Parkinson's disease patients. Despite the potential importance, no biomarker has as yet been validated. However, features such as low levels of epidermal and insulin‐like growth factors or uric acid in plasma/serum and of Aß in CSF, reduction of cerebral cholinergic innervation and metabolism measured by PET mainly in posterior areas, and hippocampal atrophy in MRI might be indicative of distinct deficits with a distinct risk of dementia in subgroups of patients. Longitudinal studies combining the existing techniques and new approaches are needed to identify patients at higher risk of dementia. © 2016 International Parkinson and Movement Disorder Society     

White matter changes in 80 mild cognitive impairment patients using magnetic resonance imaging

BACKGROUND： Many studies have suggested that one possible etiology of mild cognitive impairment is small vessel cerebrovascular disease, which is associated with small subcortical infarcts and white matter abnormalities. These white matter changes have been detected as white matter hyperintensity （WMH） using magnetic resonance imaging. WMH may be associated with frontal lobe dysfunction. OBJECTIVE： To examine white matter changes in mild cognitive impairment patients of different subtypes, and to evaluate the correlation between white matter changes and neuropsychological characteristics, demographic information, vascular risk factors, and mild cognitive impairment subtypes. DESIGN, TIME AND SETTING： The neurophysiological, comparison study was performed at the Department of Neurology Memory Clinic, Ulsan University Hospital, South Korea, between March 2007 and March 2008. PARTICIPANTS： Out of a total of 83 subjects with clinically diagnosed mild cognitive impairment at the out-patient clinic, 3 subjects with severe WMH were excluded. A total of 80 subjects were included in this study. No patients suffered from cognitive impairment induced by neurological diseases, mental disorders, or somatic diseases. In accordance with magnetic resonance imaging results, the patients were assigned to two subtypes： 56 subjects without WMH and 24 subjects with WMH. METHODS： All patients were subjected to a standard neuropsychological battery using the Korean version of the Mini-Mental State Examination, Clinical Dementia Rating, and comprehensive Seoul Neuropsychological Screening Battery. The Clinical Dementia Rating reflected general cognitive function of patients. Results from the Seoul Neuropsychological Screening Battery reflected attention, language function, visuospatial function, verbal memory, nonverbal memory, long-term memory, and frontal/executive function. Magnetic resonance imaging was used to map changes in the brain. MAIN OUTCOME MEASURES： The association between various white matter changes and neuropsychological characteristics, demographic information, vascular risk factors, and mild cognitive impairment subtypes was measured, based primarily on neuropsychological profiles using statistical methods. RESULTS： WMH was significantly associated with neuropsychological characteristics in MCI patients （P 〈 0.05 or P 〈 0.01）, in particular with frontal/executive dysfunction. WMH was significantly correlated with age （P = 0.022） and vascular risk factors （P = 0.006）, independent of gender and MCI subtypes. CONCLUSION： WMH was significantly associated with frontal/executive dysfunction in mild cognitive impairment.     

Subtypes of mild cognitive impairment in Parkinson's disease: progression to dementia.

The aim of this study was to establish the rate of progression from mild cognitive impairment (MCI) to dementia in patients with Parkinson's disease (PD). PD patients without dementia were recruited in 1997 from an ongoing prospective epidemiological study. The assessment included neurological and psychiatric examinations, a clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) criteria for dementia, and a battery of neuropsychological tests. PD was diagnosed according to established criteria, dementia was diagnosed according to the DSM-III-R criteria, and subtypes of MCI were classified according to modified Petersen's criteria. Seventy-two nondemented PD patients were included. A total of 34 were cognitively intact, whereas 38 were diagnosed with MCI (amnestic, n = 6; single nonmemory domain, n = 17; multiple domains slightly impaired, n = 15). Fifty-nine patients (82%) completed follow-up examination 4 years later, and 18 (62%) of the patients with MCI and 6 (20%) of the cognitively intact PD patients were demented (P = 0.001). Single domain nonmemory MCI and multiple domains slightly impaired MCI were associated with later development of dementia (P = 0.003; P = 0.04), whereas amnestic MCI subtype was not (P = 0.76). We conclude that patients with PD and MCI had a higher risk of developing dementia than cognitively intact PD patients, suggesting that MCI in PD is an early manifestation of dementia. However, these findings should be interpreted with caution due to the relatively small number of subjects included in this study.     

Impact of perceived stress on cognitive performance: Moderating effect of mild cognitive impairment and Alzheimer’s disease

Introduction: Stress is a well-known determinant of cognitive performance in both younger and older adults. However, the moderating effect of pathological aging on this relationship remains insufficiently documented. We hypothesize that mild cognitive impairment (MCI) and Alzheimer’s disease (AD) patients will report higher perceived stress than control older adults, when asked to complete an effortful cognitive task. We also hypothesize that the deleterious effect of perceived stress on cognitive performance is more evident in MCI and AD patients.

Method: The 131 participants consisted of: 25 functional older adults, 35 nonamnestic-MCI patients, 35 amnestic-MCI patients, and 36 AD patients. They were asked to complete the Victoria Stroop test and report their level of perceived stress at four times: before the test (i.e., baseline) and after each part of the test (three, increasingly effortful levels of cognitive requirement).

Results: Overall, perceived stress increased in the most effortful condition—except for AD patients, who reported a decline. A positive main effect of perceived stress on response latency was confirmed. However, this effect became negative in all participants when the model accounted for the difficulty of the task.

Discussion: The results suggest that the ability to perceive the stress levels generated by an effortful cognitive task may be altered in AD. They also suggest that the Stroop task may generate a form of perceived stress favoring engagement, and AD patients may not benefit from its positive effects on performance. They put into questions the usual clinical interpretations.