Cortical asymmetries in normal, mild cognitive impairment, and Alzheimer's disease

There are functional and structural neocortical hemispheric asymmetries in people with normal cognition. These asymmetries may be altered in patients with Alzheimer's disease (AD) because there is a loss of neuronal connectivity in the heteromodal cortex. The purpose of this study is to test the hypothesis that individuals with amnestic mild cognitive impairment (aMCI), mild AD, and moderate to severe AD have progressive reductions in thickness asymmetries of the heteromodal neocortex. Right-handed elderly volunteers including normal cognition (NC), aMCI, and AD underwent 3-D volume imaging for cortical thickness. Although the cortical asymmetry pattern observed in normal cognition brains was generally maintained in aMCI and AD, there was a progressive decrease in the degree of asymmetry, especially in the inferior parietal lobule. A reduction of neocortical asymmetries may be a characteristic sign that occurs in patients with AD. Future studies are needed to evaluate whether this loss is specific to AD and if measurements of asymmetry can be used as diagnostic markers and for monitoring disease progression.     

Abnormal retinal thickness in patients with mild cognitive impairment and Alzheimer's disease

In Alzheimer's disease (AD), brain lesions are marked by severe neuronal loss and retinal degeneration was previously mentioned in affected patients. Mild cognitive impairment (MCI) is a clinical syndrome that could be an early phase of AD. In this study, using optical coherence tomography (OCT), the retinal nerve fiber layer (RNFL) thickness was assessed in patients with mild AD, moderate to severe AD, amnestic MCI and control subjects. The results show that RNFL thickness is statistically reduced in patients with MCI, mild AD or moderate to severe AD compared to controls. In addition, no statistical difference was found between the results in MCI patients and mild AD patients. The RNFL seems to be involved early during the course of amnestic MCI and OCT tests could be carried out in patients with cognitive troubles.     

Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer's disease

Mild cognitive impairment (MCI) is a nosological entity proposed as an intermediate state between normal aging and dementia. MCI seems to represent an early stage of Alzheimer's disease (AD) and there is a great interest in the relationship between MCI and the progression to AD. Some studies have demonstrated an accumulation of products of free radical damage in the central nervous system and in the peripheral tissues of subjects with AD or mild cognitive impairment. The aim of the present work was to evaluate the serum levels of some enzymatic antioxidant defences like superoxide dismutase (SOD) and glutathione peroxidase (GPX), as well as lipid peroxidation markers like MDA (malondialdehyde), in MCI and AD patients, compared with age-matched healthy controls. The subjects of this study (45 patients) consisted of 15 individuals with mild cognitive impairment (MCI), 15 with Alzheimer's disease (AD) and 15 healthy age-matched controls. Biochemical analyses showed a similar decrease of the main enzymatic antioxidant defences (SOD and GPX) and increased production of lipid peroxidation marker (MDA) in the serum of the MCI and AD patients, compared to age-matched control group. This study clearly demonstrates that oxidative stress damage occurs in patients with MCI and AD. Moreover, some enzymatic markers of oxidative stress are similar in MCI and AD patients, suggesting that oxidative damage could be one important aspect for the onset of AD.     

A multimodal MRI investigation of the subventricular zone in mild cognitive impairment and Alzheimer's disease patients

The subventricular zone (SVZ) is a region that lies immediately beneath the ependymal layer on the lateral wall of the lateral ventricles, and is separated from the caudate nucleus by a layer of myelin. It contains multipotent neural stem cells. The aim of this study was to investigate the tissue around the SVZ, with the hypothesis that multimodal MRI is able to highlight the progressive disruption of tissue caused by the neurodegenerative disease in this area. We combined volumetric and diffusion tensor (DTI) imaging using a 3 T imager in a cross-sectional study including 30 patients with amnestic-mild cognitive impairment (a-MCI), 30 patients with Alzheimer's disease (AD) and 30 age- and gender-matched healthy controls (HC). Our data indicate that mean diffusivity (MD) values increase continuously from HC through a-MCI to AD in the bilateral SVZ, where most of the proliferating stem cells in the adult brain are located. This result was specific for the SVZ and could not be observed in other periventricular areas. Multimodal MRI, being able to highlight structural changes of microscopic tissue in humans in vivo, could represent a precious tool to complement histological studies of neurogenesis.     

Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer's disease

Soluble fractalkine plays a distinctive role in the inflammatory processes of the nervous system; however, the role of soluble fractalkine in Alzheimer's disease (AD) has not yet been investigated. In the present study, we evaluated the levels of plasma soluble fractalkine in patients with mild cognitive impairment (MCI), patients with AD and healthy controls. We also investigated the changes in the levels of plasma soluble fractalkine in patients with AD. A total of 102 patients with cognitive impairment, including 51 patients with MCI, 51 patients with AD, and 57 healthy control subjects, were enrolled in this study. The Mini-Mental Status Examination (MMSE) was used to evaluate the severity of cognitive impairment in patients with MCI and AD. The levels of plasma soluble fractalkine were measured using a specific enzyme-linked immunosorbent assay. There were significant group differences in the levels of plasma soluble fractalkine between the MCI, AD, and control groups. Post hoc analyses revealed significant differences between the MCI and control groups, the AD and control groups, and the MCI and AD groups. The level of plasma soluble fractalkine was significantly greater in the patients with mild to moderate AD than in the patients with severe AD. In addition, there was a positive correlation between MMSE score and plasma soluble fractalkine level in the patients with AD. This study provides preliminary evidence that soluble fractalkine is involved in the pathogenesis of AD.     

Structural and functional neural correlates of visuospatial information processing in normal aging and amnestic mild cognitive impairment

Our understanding of cognitive changes related to human aging and their underlying neural processes is challenged by the distinction between normal and pathological aging. In our study, the neural correlates of visuospatial working memory (VSWM) in young persons (YC), healthy older adults (HC) and patients with amnestic mild cognitive impairment (aMCI) were investigated. Effects of the genetic risk factor apolipoprotein E (ApoE) ε4 on a VSWM task were analyzed for HC and aMCI patients. Higher cortical activation in extrastriate occipital regions and significantly decreased brain volumes in frontoparietal areas were observed in HC compared with young persons. Also, reduced cortical activation in the right middle frontal gyrus and superior frontal gyrus was observed in aMCI-patients compared with HC. Thus, attenuated cortical activation during VSWM tasks is related to the formation of aMCI and may serve as an early marker for cognitive decline. In contrast to previous studies, no significant apolipoprotein E-linked differences were found between HC and aMCI groups.     

Hippocampal and cortical atrophy in amyloid-negative mild cognitive impairments: comparison with amyloid-positive mild cognitive impairment

Although patients with amnestic mild cognitive impairment (aMCI) are at higher risk of developing Alzheimer's disease (AD), their pathologies could be heterogeneous. We aimed to evaluate structural changes in amyloid-negative and amyloid-positive aMCI patients. Forty-eight aMCI patients who underwent Pittsburgh compound B (PiB) positron emission tomography were recruited. They were classified as PiB (−) aMCI (N = 16) and PiB (+) (N = 32). Hippocampal shape and regional cortical thickness were compared with 41 subjects with normal cognition (NC). Relative to NC, PiB(−) aMCI exhibited hippocampal deformity in the right cornu ammonis 1, whereas PiB(+) aMCI exhibited hippocampal deformity in bilateral subiculum and cornu ammonis 1 subregions. Relative to NC, PiB(−) aMCI showed cortical thinning in the left medial prefrontal and right anterior temporal regions, whereas PiB(+) aMCI exhibited cortical thinning in bilateral medial temporal regions, temporoparietal junctions and precuneus, and prefrontal cortices. Our findings suggest that structural changes in PiB(−) aMCI might be due to several possible pathologic changes, whereas structural changes in PiB(+) aMCI reflect AD-like structural changes.     

Event-related synchronization of alpha activity in early Alzheimer's disease and mild cognitive impairment: an MEG study combining beamformer and group comparison

In patients with Alzheimer's disease (AD), it is sometimes challenging to identify typical findings in electroencephalography (EEG) or magnetoencephalography (MEG) such as a slowing of the posterior dominant activity or an increase in slow activity. In this MEG study, we evaluated the event-related synchronization (ERS) of alpha activity after eye closing in patients with early AD and mild cognitive impairment (MCI) who presented no slow MEG pattern. Thirteen patients with probable AD and thirteen patients with MCI, who met NINCDS-ADRDA and Petersen's diagnostic criteria, respectively, were enrolled. We also selected fourteen age-matched normal control subjects. MEG activity was acquired during eye-open and eye-closed states. The ERS after eye closing within 8-15Hz frequency band was calculated and its cortical source was superimposed on the individual's MRI by using the beamformer implemented in Brain Electrical Source Analysis (BESA). The Source image was converted into a standardized image, and group comparisons across patients with AD, MCI and controls were performed using BrainVoyager QX. The averaged ERS was observed dominantly in posterior regions in all three groups. Significant difference in ERS was observed only for the comparison between AD patients and controls, with AD patients showing increased ERS in frontal regions. Frontal shift of posterior alpha activity was observed clearly in AD patients using the combination of beamformer and group comparison.     

Diffusion tensor imaging and Tract-Based Spatial Statistics in Alzheimer's disease and mild cognitive impairment

We aimed to explore the changes in fractional anisotropy (FA) in subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD) by analyzing diffusion tensor imaging (DTI) data using the Tract-Based Spatial Statistics (TBSS). DTI data were collected from 17 AD patients, 27 MCI subjects and 19 healthy controls. Voxel-based analysis with TBSS was used to compare FA among the three groups. Additionally, guided by TBSS findings, a region of interest (ROI)-based analysis along the TBSS skeleton was performed on group-level and the accuracy of the method was assessed by the back-projection of ROIs to the native space FA. Neurofiber tracts with decreased FA included: the parahippocampal white matter, cingulum, uncinate fasciculus, inferior and superior longitudinal fasciculus, corpus callosum, fornix, tracts in brain stem, and cerebellar tracts. Quantitative ROI-analysis further demonstrated the significant decrease on FA values in AD patients relative to controls whereas FA values of MCI patients were found in between the controls and AD patients. We conclude that TBSS is a promising method in examining the degeneration of neurofiber tracts in MCI and AD patients.     

Increased plasma levels of heat shock protein 70 in patients with vascular mild cognitive impairment

Heat shock proteins (Hsps) have been regarded as cytoprotectants that protect brain cells from damage encountered following cerebral ischemia or during the progression of neurodegenerative diseases. In this study, we assessed the plasma Hsp70 and Hsp27 levels in not cognitively impaired (NCI) subjects and in patients with mild cognitive impairment (MCI), vascular mild cognitive impairment (VMCI), and probable Alzheimer's disease (AD). Comparison of the plasma Hsp70 and Hsp27 levels of the 4 groups revealed that only the plasma Hsp70 level of VMCI patients (14.11 ng/ml) was significantly higher than that of NCI subjects (11.32 ng/ml), MCI patients (10.16 ng/ml), and patients with probable AD (10.16 ng/ml) after adjustment of age, sex, and education (F=4.231, d.f.=3, p=0.008). Furthermore, there was no difference in plasma Hsp27 levels among the 4 groups. These findings suggest that the plasma Hsp70 level may be related to vascular factors or inflammation.     

Differences in and correlations between cognitive abilities and brain volumes in healthy control,mild cognitive impairment,and Alzheimer disease groups

The purpose of this study is to investigate differences in and correlations between cognitive abilities and brain volumes in healthy control (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) groups. The Korean Version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD‐K), which is used to diagnose AD, was used to measure the cognitive abilities of the study subjects, and the volumes of typical brain components related to AD diagnosis—cerebrospinal fluid (CSF), gray matter (GM), and white matter (WM)—were acquired. Of the CERAD‐K subtests, the Boston Naming Test distinguished significantly among the HC, MCI, and AD groups. GM and WM volumes differed significantly among the three groups. There was a significant positive correlation between Boston Naming Test scores and GM and WM volumes. In conclusion, the Boston Naming Test and GM and WM brain volumes differentiated the three tested groups accurately, and there were strong correlations between Boston Naming Test scores and GM and WM volumes. These results will help to establish a test method that differentiates the three groups accurately and is economically feasible. Clin. Anat. 29:473–480, 2016. © 2016 Wiley Periodicals, Inc.     

Conceptual implicit memory impaired in amnestic mild cognitive impairment patient

Explicit memory has been well proven to be impaired in amnestic mild cognitive impairment (aMCI), and conceptual implicit memory is impaired in Alzheimer's disease. However, it is unclear whether implicit memory is affected in aMCI. In the present study, 35 patients with aMCI and 35 healthy elderly subjects were administered a neuropsychological battery of tests including conceptual and perceptual implicit memory tasks (category exemplar generation, image identification) as well as explicit memory tasks. Patients with aMCI exhibited impairment in explicit memory tasks and selective impairment in conceptual priming tasks, while the effect of perceptual priming was preserved. More importantly, category exemplar generation task priming, but not perceptual priming, was positively correlated with verbal fluency test performance in the aMCI group. The dissociation between the 2 components of implicit priming suggests that conceptual priming impairment in aMCI patients may be related to frontal lobe dysfunction.     

A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease

We reviewed case-control studies of diffusion tensor imaging (DTI) in patients with Alzheimer's dementia (AD) and mild cognitive impairment (MCI), in order to establish the relative severity and location of white matter microstructural changes. EMBASE and MEDLINE were searched using the keywords, ([“diffusion tensor”] and [“Alzheimer*” or “mild cognitive impairment”]), as were reference lists of relevant papers. Forty-one diffusion tensor imaging studies contained data that were suitable for inclusion. Group means and standard deviations for fractional anisotropy and mean diffusivity, or p values from 2-sample tests, were extracted and pooled, using standard methods of meta-analysis and metaregression. Fractional anisotropy was decreased in AD in all regions except parietal white matter and internal capsule, while patients with MCI had lower values in all white matter regions except parietally and occipitally. Mean diffusivity was increased in AD in all regions, and in MCI in all but occipital and frontal regions.     

Biomarkers of oxidative and nitrosative damage in Alzheimer's disease and mild cognitive impairment

Alzheimer's disease (AD) is the most common type of dementia in the elderly. Products of oxidative and nitrosative stress (OS and NS, respectively) accumulate with aging, which is the main risk factor for AD. This provides the basis for the involvement of OS and NS in AD pathogenesis. OS and NS occur in biological systems due to the dysregulation of the redox balance, caused by a deficiency of antioxidants and/or the overproduction of free radicals. Free radical attack against lipids, proteins, sugars and nucleic acids leads to the formation of bioproducts whose detection in fluids and tissues represents the currently available method for assessing oxidative/nitrosative damage. Post-mortem and in-vivo studies have demonstrated an accumulation of products of free radical damage in the central nervous system and in the peripheral tissues of subjects with AD or mild cognitive impairment (MCI). In addition to their individual role, biomarkers for OS and NS in AD are associated with altered bioenergetics and amyloid-beta (Aβ) metabolism. In this review we discuss the main results obtained in the field of biomarkers of oxidative/nitrosative stress in AD and MCI in humans, in addition to their potential role as a tool for diagnosis, prognosis and treatment efficacy in AD.     

Increased tau protein differentiates mild cognitive impairment from geriatric depression and predicts conversion to dementia

Significantly increased cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated at threonine 181 tau (p-tau) levels were frequently found in patients with mild cognitive impairment (MCI) who have an increased risk of developing Alzheimer's disease (AD). Though MCI often overlaps with depressive symptoms making early diagnosis difficult, to date no CSF marker has been probed to support the differential diagnosis of geriatric major depressive disorder and MCI eventually converting to AD. CSF levels of t-tau and p-tau were determined by ELISA in 80 subjects with MCI (aging associated cognitive decline criteria), 54 patients with major depression and 24 cognitively healthy controls. Patients were reassessed after a follow-up period of at least 12 month. During follow-up, 29% of the MCI patients but only one patient with major depression converted to AD. Already at baseline converters to AD were characterized by significantly higher t-tau and p-tau levels compared to non-converters and the other diagnostic groups. Our findings demonstrate that both, CSF t-tau and p-tau levels facilitate the differential diagnosis of MCI and are of prognostic value.     

Measurements of medial temporal lobe atrophy for prediction of Alzheimer's disease in subjects with mild cognitive impairment

Our aim was to compare the predictive accuracy of 4 different medial temporal lobe measurements for Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI). Manual hippocampal measurement, automated atlas-based hippocampal measurement, a visual rating scale (MTA-score), and lateral ventricle measurement were compared. Predictive accuracy for AD 2 years after baseline was assessed by receiver operating characteristics analyses with area under the curve as outcome. Annual cognitive decline was assessed by slope analyses up to 5 years after baseline. Correlations with biomarkers in cerebrospinal fluid (CSF) were investigated. Subjects with MCI were selected from the Development of Screening Guidelines and Clinical Criteria for Predementia AD (DESCRIPA) multicenter study (n = 156) and the single-center VU medical center (n = 172). At follow-up, area under the curve was highest for automated atlas-based hippocampal measurement (0.71) and manual hippocampal measurement (0.71), and lower for MTA-score (0.65) and lateral ventricle (0.60). Slope analysis yielded similar results. Hippocampal measurements correlated with CSF total tau and phosphorylated tau, not with beta-amyloid 1–42. MTA-score and lateral ventricle volume correlated with CSF beta-amyloid 1–42. We can conclude that volumetric hippocampal measurements are the best predictors of AD conversion in subjects with MCI.