Discourse changes in early Alzheimer disease,mild cognitive impairment,and normal aging

The purpose of this study was to determine the sensitivity of discourse gist measures to the early cognitive-linguistic changes in Alzheimer disease (AD) and in the preclinical stages. Differences in discourse abilities were examined in 25 cognitively normal adults, 24 adults with mild probable AD, and 20 adults with mild cognitive impairment (MCI) at gist and detail levels of discourse processing. The authors found that gist and detail levels of discourse processing were significantly impaired in persons with AD and MCI as compared with normal control subjects. Gist-level discourse processing abilities showed minimal overlap between cognitively normal control subjects and those with mild AD. Moreover, the majority of the persons with MCI performed in the range of AD on gist measures. These findings indicate that discourse gist measures hold promise as a diagnostic complement to enhance early detection of AD. Further studies are needed to determine how early the discourse gist deficits arise in AD.     

Somatosensory responses in normal aging, mild cognitive impairment, and Alzheimer’s disease

As a part of a larger study of normal aging and Alzheimer’s disease (AD), which included patients with mild cognitive impairment (MCI), we investigated the response to median nerve stimulation in primary and secondary somatosensory areas. We hypothesized that the somatosensory response would be relatively spared given the reported late involvement of sensory areas in the progression of AD. We applied brief pulses of electric current to left and right median nerves to test the somatosensory response in normal elderly (NE), MCI, and AD. MEG responses were measured and were analyzed with a semi-automated source localization algorithm to characterize source locations and timecourses. We found an overall difference in the amplitude of the response of the primary somatosensory source (SI) based on diagnosis. Across the first three peaks of the SI response, the MCI patients exhibited a larger amplitude response than the NE and AD groups (P < 0.03). Additional relationships between neuropsychological measures and SI amplitude were also determined. There was no significant difference in amplitude for the contralateral secondary somatosensory source across diagnostic category. These results suggest that somatosensory cortex is affected early in the progression of AD and may have some consequence on behavioral and functional measures.     

Patterns of verbal memory performance in mild cognitive impairment, Alzheimer disease, and normal aging.

OBJECTIVE: Individuals with mild cognitive impairment (MCI) typically demonstrate memory loss that falls between normal aging (NA) and Alzheimer disease (AD), but little is known about the pattern of memory dysfunction in MCI. METHOD: To explore this issue, California Verbal Learning Test (CVLT) performance was examined across groups of MCI, AD, and NA. RESULTS: MCI subjects displayed a pattern of deficits closely resembling that of AD, characterized by reduced learning, rapid forgetting, increased recency recall, elevated intrusion errors, and poor recognition discriminability with increased false-positives. MCI performance was significantly worse than that of controls and better than that of AD patients across memory indices. Although qualitative analysis of CVLT profiles may be useful in individual cases, discriminant function analysis revealed that delayed recall and total learning were the best aspects of learning/memory on the CVLT in differentiating MCI, AD, and NA. CONCLUSIONS: These findings support the position that amnestic MCI represents an early point of decline on the continuum of AD that is different from normal aging.     

Brain erythropoietin receptor expression in Alzheimer disease and mild cognitive impairment

Cellular mechanisms conferring neuroprotection in the brains of patients with Alzheimer disease (AD) remain incompletely understood. Erythropoietin (Epo) and the erythropoietin receptor (EpoR) are expressed in neural tissues and protect against oxidative and other stressors in various models of brain injury and disease. Our objective in this study was to determine whether EpoR is upregulated in the brains of persons with sporadic AD and mild cognitive impairment (MCI). Postmortem hippocampus and temporal cortex from subjects with AD, MCI, and no cognitive impairment (NCI) were procured from the Religious Orders Study. Total immunoreactive EpoR protein was determined by Western blotting. Astrocytes expressing immunoreactive EpoR were quantified in 4 temporal and 6 hippocampal regions, and correlated with clinical, neuropsychologic, and neuropathologic indices. Total immunoreactive EpoR protein was markedly increased in AD and MCI temporal cortex versus NCI tissues. Composite measures of glial EpoR expression in temporal cortex layers I to IV were significantly greater in the MCI group compared with the NCI and AD groups. Hippocampal EpoR scores were increased in persons with MCI and AD relative to those with NCI. There was substantial subregional heterogeneity in disease-related EpoR expression patterns in AD and MCI temporal cortex and hippocampus. There was no association of EpoR-positive astrocytes with summary measures of global cognition or AD pathology. We conclude that upregulation of EpoR in temporal cortical and hippocampal astrocytes is an early, potentially neuroprotective, event in the pathogenesis of sporadic AD.     

Differentiating between Alzheimer's disease,amnestic mild cognitive impairment,and normal aging via diffusion kurtosis imaging

Diffusion kurtosis imaging can be used to assess pathophysiological changes in tissue structure and to diagnose central nervous system diseases. However, its sensitivity in assessing hippocampal differences between patients with Alzheimer's disease and those with amnestic mild cognitive impairment has not been characterized. Here, we examined 20 individuals with Alzheimer's disease(11 men and 9 women, mean73.2 ± 4.49 years), 20 with amnestic mild cognitive impairment(10 men and 10 women, mean 71.55 ± 4.77 years), and 20 normal controls(11 men and 9 women, mean 70.45 ± 5.04 years). We conducted diffusion kurtosis imaging, using a 3.0 T magnetic resonance scanner,to compare hippocampal differences among the three groups. The results demonstrated that the right hippocampal volume and bilateral mean kurtosis were remarkably smaller in individuals with Alzheimer's disease compared with those with amnestic mild cognitive impairment and normal controls. Further, the mean kurtosis was lower in the amnestic mild cognitive impairment group compared with the normal control group. The mean diffusion in the left hippocampus was lower in the Alzheimer's disease group than in the amnestic mild cognitive impairment and normal control groups, while the mean diffusion in the right hippocampus was lower in the Alzheimer's disease group than in the normal control group. Fractional anisotropy was similar among the three groups. These results verify that bilateral mean kurtosis and mean diffusion are sensitive to the diagnosis of Alzheimer's disease and amnestic mild cognitive impairment. This study was approved by the Ethics Review Board of Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, China on May 4, 2010(approval No. 2010(C)-6).     

Magnetization transfer imaging in normal aging,mild cognitive impairment,and Alzheimer's disease

The purpose of this study was to assess whether structural brain damage as detected by volumetric magnetization transfer imaging (MTI) is present in mild cognitive impairment (MCI) and Alzheimer's disease (AD) and, if so, whether these abnormalities are global in character or restricted to the temporal lobe. Volumetric MTI analysis of the whole brain and temporal and frontal lobes was performed in 25 patients with probable AD, in 13 patients with MCI, and in 28 controls. Magnetization transfer ratio (MTR) histograms were produced, from which we derived measures for structural brain damage and atrophy. The peak heights of the MTR histograms of MCI and AD patients were lower than those of controls for the whole brain and temporal and frontal lobes, reflecting structural brain damage. AD patients had more atrophy than controls in all regions that were studied. MCI patients differed from controls for temporal lobe atrophy only. Volumetric MTI demonstrates structural changes that are related to cognitive decline in large parts of the brain of AD patients. Moreover, structural changes also were observed in MCI patients, indicating that widespread brain damage can be demonstrated before patients are clinically demented.     

Volumetric MRI measurements can differentiate Alzheimer's disease,mild cognitive impairment,and normal aging

BACKGROUND: Volumetric magnetic resonance imaging (MRI) has been extensively studied in the last decade as a method to help with the clinical diagnosis of Alzheimer's disease (AD). In recent years, researchers have also started investigating if that technique would be useful to identify individuals with mild cognitive impairment (MCI), differentiating them from AD patients and from normal elderly controls. This research project was planned to assess the accuracy of volumetric MRI to differentiate those groups of individuals. METHOD: The investigation involved 39 patients with diagnosis of mild to moderate dementia in AD, according to the criteria of the NINCDS-ADRDA, DSM-III-R, and ICD-10; 21 subjects with complaints of cognitive decline without other psychiatric disorders (MCI); and 20 normal elderly controls. All the subjects were submitted to a standard protocol, including volumetric MRI evaluations. RESULTS: The results indicated that all regions of interest measured (amygdala, hippocampus, and parahippocampal gyrus) were significantly different (p < .005) in AD patients compared to MCI subjects and controls. The left volumetric measures (amygdala, hippocampus, and parahippocampal gyrus) were also significantly different between the MCI subjects and controls (p < .05). The discriminant function analysis correctly classified 88.14% of the AD patients and controls, 81.67% of AD patients and MCI subjects, and 80.49% of the MCI subjects and controls. CONCLUSIONS: The results suggest that measures of medial temporal lobe regions are useful to identify mild to moderate AD patients and MCI subjects, separating them from normal elderly individuals.     

Hippocampal atrophy and ventricular enlargement in normal aging, mild cognitive impairment (MCI), and Alzheimer Disease

Alzheimer disease (AD) is the most common type of dementia worldwide. Hippocampal atrophy and ventricular enlargement have been associated with AD but also with normal aging. We analyzed 1.5-T brain magnetic resonance imaging data from 46 cognitively normal elderly individuals (NC), 33 mild cognitive impairment and 43 AD patients. Hippocampal and ventricular analyses were conducted with 2 novel semiautomated segmentation approaches followed by the radial distance mapping technique. Multiple linear regression was used to assess the effects of age and diagnosis on hippocampal and ventricular volumes and radial distance. In addition, 3-dimensional map correction for multiple comparisons was made with permutation testing. As expected, most significant hippocampal atrophy and ventricular enlargement were seen in the AD versus NC comparison. Mild cognitive impairment patients showed intermediate levels of hippocampal atrophy and ventricular enlargement. Significant effects of age on hippocampal volume and radial distance were seen in the pooled sample and in the NC and AD groups considered separately. Age-associated differences were detected in all hippocampal subfields and in the frontal and body/occipital horn portions of the lateral ventricles. Aging affects both the hippocampus and lateral ventricles independent of AD pathology, and should be included as covariate in all structural, hippocampal, and ventricular analyses when possible.     

Reaction times and performance variability in normal aging, mild cognitive impairment, and Alzheimer's disease

This study evaluated whether reaction times (RT) and performance variability are potential markers for the early detection of Alzheimer's disease (AD). Cognitively healthy elderly (n = 218), persons with amnestic MCI (a-MCI) (n = 29) and patients with AD (n = 50) were examined with RT tasks with increasing complexity, subdividing RT into a decision and a movement component. Persons with cognitive deterioration demonstrated more intra-individual variability and more slowing than cognitively healthy elderly. The slowing in AD affects both the cognitive and the motor component, while performance variability mainly affects the cognitive component of the RT. Although in a-MCI not all differences reached statistical significance, primarily the cognitive component of the RT is affected in a-MCI. Intra-individual variability and RT of the complex tasks are the best predictors for a-MCI and AD status, respectively. We conclude that performance variability can be regarded as a useful preclinical marker for AD.     

Manual validation of FreeSurfer's automated hippocampal segmentation in normal aging,mild cognitive impairment,and Alzheimer Disease subjects

Hippocampal volume is reduced in Alzheimer Disease (AD) and has been proposed as a possible surrogate biomarker to aid early diagnosis. Whilst automated methods to segment the hippocampus from magnetic resonance images are available, manual segmentation, in spite of being time-consuming and unsuitable for large samples, is still the standard. In order to study the validity of FreeSurfer's automated method, we compared hippocampal automated measures with manual tracing in a sample composed of healthy elderly (N = 41), Mild Cognitive Impairment (MCI) (N = 23), and AD (N = 25) subjects. Percent volume overlap, percent volume difference, correlations, and Bland–Altman plots were studied. Automated measures were slightly larger than hand tracing ones (mean difference 10%). Percent volume overlap showed good results, but was far from perfect (78%). Manual and automated volume correlations were approximately 0.84 and the Bland–Altman analysis showed acceptable interchangeability of methods. Within-group analysis demonstrated that patient samples obtained smaller values in validity indexes than controls. Globally, FreeSurfer's automated hippocampal volumetry showed adequate validity when compared to manual tracing, with a tendency to overestimation. Nevertheless, the greater difference between automated and manual segmentation in atrophic brains suggests that studies in AD based on this software could be more likely to produce false negatives.     

Diffusion tensor imaging in Alzheimer disease and mild cognitive impairment

A wide range of imaging studies provides growing support for the potential role of diffusion tensor imaging (DTI) in evaluating microstructural white matter integrity in Alzheimer disease (AD) and mild cognitive impairment (MCI). Our review aims to present DTI principles, post-processing and analysis frameworks and to report the results of particular studies.The distribution of AD-related white matter abnormalities is widely discussed in the light of deteriorated connectivity within certain tracts due to secondary white matter degeneration; primary alterations are also assumed to contribute to the pattern. The question whether it is more effective to assess the whole-brain diffusion or to directly concentrate on specific regions remains an interesting issue. Assessing white matter microstructure alterations, as evaluated by group-level differences of tensor-derived parameters, may be a promising neuroimaging tool for differential diagnosis between AD, MCI and other cognitive disorders, as well as being particularly helpful in the interpretation of underlying pathological processes.     

Olfactory tau pathology in Alzheimer disease and mild cognitive impairment

OBJECTIVE: To examine the occurrence of tau pathology in the olfactory system in aged subjects and its relation to the severity of Alzheimer disease (AD) pathology. MATERIAL AND METHODS: 273 autopsy cases (167 female, 106 male, aged 61-102, mean 83.2+/-4.5 SD years) underwent a standard neuropathological assessment with immuno-histochemical study of tau and Abeta amyloid in the olfactory bulb and nerve, and diagnosis of AD using established consensus criteria including Braak staging of neuritic AD pathology. RESULTS: All cases of definite AD (Braak stages 5 and 6, n = 96) showed large numbers of neuropil threads and neurofibrillary tangles, with amyloid deposits in 50%, and neuritic plaques only in two cases. Braak stage 4 (n = 73) was associated with tau pathology in the olfactory system in 90.4 and amyloid deposits in 9%, Braak stage 3 (n = 56) with mainly mild to moderate olfactory tau lesions in 44.6 and Abeta deposits in 9%. Braak stage 2 (n = 22) showed olfactory tau pathology in 36.4% without amyloid deposits, whereas Braak stages 0 and 1 (n = 25) were all negative. Olfactory tau pathology showed highly significant correlation with neuritic Braak staging in the brain, while both scores showed significant but low correlation with age. CONCLUSIONS: These data confirm previous studies demonstrating considerable tau pathology in the olfactory system in all definite AD cases, in more than 2/3 of limbic AD and in more than 1/3 of elderly individuals with or without mild cognitive impairment associated with Braak stage 2. Clinical dementia correlated with both Braak and olfactory tau scores, indicating that both are associated with a high risk of cognitive decline.     

Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease

OBJECTIVES: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. CONCLUSION: Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.     

Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease

BACKGROUND: Immunoreactivity for several chemokines and for their related receptors has been demonstrated in resident cells of the central nervous system, and the up-regulation of some of them is associated with pathological changes found in Alzheimer disease (AD). OBJECTIVE: To determine interferon-gamma-inducible protein 10 (IP-10), monocyte chemotactic protein 1 (MCP-1), and interleukin 8 (IL-8) levels in cerebrospinal fluid (CSF) from subjects with amnestic mild cognitive impairment (MCI) and patients with AD as compared with age-matched controls. PATIENTS: Thirty-eight subjects with amnestic MCI, 36 patients with AD, and 41 age-matched subjects with noninflammatory affections of the nervous system. DESIGN: Evaluation of CSF chemokine production at time of diagnosis of MCI and AD; correlation with clinical and personal data. Longitudinal evaluation of subjects with MCI until conversion to AD. RESULTS: Cerebrospinal fluid IP-10 concentration was significantly increased in patients with MCI and mild AD but not in patients with severe AD (Mini-Mental State Examination score <15), whereas MCP-1 and IL-8 levels were increased in patients with MCI and all patients with AD. A significant positive correlation between Mini-Mental State Examination score and CSF IP-10 or MCP-1 concentration was observed in patients with AD. No correlation between IP-10 levels and age was found, whereas MCP-1 and IL-8 levels correlated positively with age. Out of 38 subjects with MCI, 19 developed AD within a 1- to 3-year follow-up. CONCLUSIONS: The presence of inflammatory molecules is likely to be a very early event in AD pathogenesis, even preceding the clinical onset of the disease, as demonstrated by subjects with MCI who developed AD over time. Interferon-gamma-inducible protein 10 is specifically increased in MCI and seems to decrease with the progression of AD, whereas MCP-1 and IL-8 are up-regulated also in late stages of the disease, suggesting a role in phases in which neurodegeneration is prevalent.     

Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease

Transactive response DNA binding protein 43 (TDP-43) plays a central role in the neuropathology of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, but the relationship between TDP-43 abnormalities and Alzheimer disease (AD) remains unclear. To determine whether TDP-43 can serve as a neuropathologic marker of AD, we performed biochemical characterization and quantification of TDP-43 in homogenates from parietal neocortex of subjects with aclinical diagnosis of no cognitive impairment (NCI, n = 12), mild cognitive impairment (MCI, n = 12), or AD (n = 12). Immunoblots revealed increased detergent-insoluble TDP-43 in the cortex of 0, 3, and 6 of the 12 individuals with NCI, MCI, or AD, respectively. Detergent-insoluble TDP-43 was positively correlated with the accumulation of soluble Aβ42, amyloid plaques, and paired helical filamenttau. In contrast, phospho-TDP-43 was decreased in the cytosolic fraction and detergent-soluble membrane/nuclear fraction from AD patients and correlated with antemortem cognitive function.Immunofluorescence analysis confirmed that the frequencies of individuals with TDP-43 or phospho-TDP-43 cytoplasmic inclusions were higher in AD than in NCI, with MCI at an intermediate level. These data indicate that abnormalities of TDP-43 occur in an important subset of MCI and AD patients and that they correlate with the clinical and neuropathologic features of AD.