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.     

Conversion from mild cognitive impairment to probable Alzheimer's disease predicted by brain magnetic resonance spectroscopy

OBJECTIVE: Mild cognitive impairment has been regarded as a pre-Alzheimer condition, but some patients do not develop dementia. Given the available therapies for Alzheimer's disease, early diagnosis is of paramount importance. The authors' objective was to determine whether findings from magnetic resonance spectroscopy (MRS) of the hippocampus and other cortical areas would predict conversion from amnestic mild cognitive impairment to probable Alzheimer's disease. METHOD: A longitudinal inception cohort of 53 consecutive and incident subjects fulfilling the criteria of amnestic mild cognitive impairment was followed for a mean period of 3 years. At baseline, a neuropsychological examination (Mini-Mental State Examination, Blessed Dementia Rating Scale, Clinical Dementia Rating, verbal fluency test, and memory tests) and standard blood tests were performed, and three cortical areas were examined by proton MRS: left hippocampus, right parietal cortex, and left occipital cortex. The patients were evaluated periodically to detect conversion to probable Alzheimer's disease. The statistical analysis of predictions was based on receiver operating characteristic curves. RESULTS: By the follow-up assessment that occurred on average after 3 years, 29 patients (55%) had developed probable Alzheimer's disease. An occipital cortex N-acetylaspartate/creatine ratio < or =1.61 predicted dementia at 100% sensitivity and 75% specificity (area under the curve=0.91, 95% CI=0.80-0.97). The positive predictive value was 83%, and the negative predictive value was 100%, with an overall cross-validated classification accuracy of 88.7%. None of the values in the hippocampus and parietal cortex had significant predictive value. CONCLUSIONS: MRS of the brain performed on patients with mild cognitive impairment is a valuable tool in predicting conversion to probable Alzheimer's disease. Occipital values were more reliable than hippocampal values in this prediction.     

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.     

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.     

Abnormal salience network in normal aging and in amnestic mild cognitive impairment and Alzheimer's disease

The salience network (SN) serves to identify salient stimuli and to switch between the central executive network (CEN) and the default‐mode network (DMN), both of which are impaired in Alzheimer's disease (AD)/amnestic mild cognitive impairment (aMCI). We hypothesized that both the structural and functional organization of the SN and functional interactions between the SN and CEN/DMN are altered in normal aging and in AD/aMCI. Gray matter volume (GMV) and resting‐state functional connectivity (FC) were analyzed from healthy younger (HYC) to older controls (HOC) and from HOC to aMCI and AD patients. All the SN components showed significant differences in the GMV, intranetwork FC, and internetwork FC between the HYC and HOC. Most of the SN components showed differences in the GMV between the HOC and AD and between the aMCI and AD. Compared with the HOC, AD patients exhibited significant differences in intra‐ and internetwork FCs of the SN, whereas aMCI patients demonstrated differences in internetwork FC of the SN. Most of the GMVs and internetwork FCs of the SN and part of the intranetwork FC of the SN were correlated with cognitive differences in older subjects. Our findings suggested that structural and functional impairments of the SN may occur as early as in normal aging and that functional disconnection between the SN and CEN/ DMN may also be associated with both normal aging and disease progression. Hum Brain Mapp 35:3446–3464, 2014. © 2013 Wiley Periodicals, Inc .     

Predictive utility of apolipoprotein E genotype for Alzheimer disease in outpatients with mild cognitive impairment

BACKGROUND: In cognitively impaired patients without dementia, the utility of apolipoprotein E (APOE) genotyping is unclear. OBJECTIVE: To evaluate the predictive utility of the APOE epsilon4 genotype for conversion to probable Alzheimer disease (AD). DESIGN: Naturalistic, longitudinal study. SETTING: Memory disorders outpatient clinic. PATIENTS: A total of 136 patients with memory complaints were determined to have mild cognitive impairment and were evaluated every 6 months. Fifty-seven age- and sex-matched healthy controls were evaluated annually. MAIN OUTCOME MEASURES: Primary outcome measures included conversion to AD. Secondary outcome measures included change over time in Mini-Mental State Examination (MMSE) score and Selective Reminding Test (SRT) delayed recall score. RESULTS: The APOE epsilon4 allele was present in 25% of patients and 21% of healthy controls. During a mean +/- SD follow-up of 35.2 +/- 24.3 months, 35 of 136 patients converted to AD. APOE epsilon4 carrier status did not differ between converters (31%) and nonconverters to AD (23%, P = .3) and did not affect the time trend in MMSE or SRT scores in the entire sample. Four of 5 APOE epsilon4 homozygotes converted to AD compared with 7 of 29 heterozygotes (P = .02). In a Cox proportional hazards model stratified by age quartiles, after controlling for sex, education, MMSE score, and SRT delayed recall score, APOE epsilon4 increased the risk of AD in patients 70 to 85 years old (n = 57; risk ratio, 2.77; 95% confidence interval, 1.1-7.3; P = .03) but not in patients 55 to 69 years old (n = 79; P = .7). CONCLUSIONS: APOE epsilon4 carrier status was associated with conversion to AD in older outpatients after controlling for known demographic and clinical risk factors, and APOE epsilon4 homozygosity was associated with increased risk of conversion to AD. However, APOE epsilon4 carrier status by itself did not predict cognitive decline or conversion to AD, indicating that APOE genotyping in patients with mild cognitive impairment may have limited clinical applicability for prediction of outcome.     

Regional quantification of white matter hyperintensity in normal aging, mild cognitive impairment, and Alzheimer's disease

BACKGROUND/AIMS: A quantitative method was applied to measure the volume of white matter hyperintensity (WMH) in different brain regions of subjects with Alzheimer's disease (AD), mild cognitive impairment (MCI) and normal healthy age-matched controls, and the relationship between regional WMH and age and cognitive function was investigated. METHODS: Fifty-six subjects were included in this study, 27 AD, 15 MCI and 14 normal age-matched controls. A user-friendly software was developed for WMH quantification in frontal, temporal, and parieto-occipital lobes. Mini-Mental State Examination and cognitive scores in performing naming, language fluency, and memory tasks were obtained for correlation analysis. RESULTS: AD patients had the greatest total WMH volume, followed by MCI, then controls. However, there was a large variation within each group, and the difference did not reach a significant level. There was a positive linear correlation between the total WMH (p = 0.031) and the frontal WMH (p = 0.006) vs. age. After age correction the Boston Naming Test scores were negatively correlated with the total WMH volume in the AD (p = 0.03) and the control (p = 0.03) groups, and with the frontal WMH in controls (p = 0.01). CONCLUSION: We demonstrated a quantitative analysis method to measure regional WMH. Although WMH was not strongly associated with disease severity or cognition, it may provide a characteristic neuroimaging parameter in the study of AD development.     

Patterns of cognitive impairment and apolipoprotein genotype in persons with Alzheimer's disease

The aim of this study was to test the possible relationship between patterns of cognitive deficits--especially impairment of memory processes--and ApoE genotype in patients with AD. Fifty seven right-handed subjects (31 males and 26 females) were tested in this study. The age of subjects ranged from 50 to 79, the education lasted from 11 to 16 years. All subjects were diagnosed as probable AD patients on the basis of DSM IV and NINCDS-ADRDA criteria. Each subject was examined for: 1) ApoE genotype, 2) general level of activity (GDS and MMSE), 3) neuropsychological evaluation of cognitive processes, using full test battery. 37 patients had at least one of ApoE epsilon 4 allele (e2/4, 3 and 4/4) and 20 patients had none of ApoE 4 allele (e 2/3 and 3/3). The group of tested subjects were subdivided into 2 groups. The first group was comprised by 31 patients with 3-rd stage (according to GDS) of mental activity. Twenty six patients with 4-th stage were included into the second group. Those subgroups did not significantly differ if age, education, gender or ApoE allele were considered. Experimental data were normalized and then analyzed using a statistical package SPSS/PC+. The analysis of variance showed that the type of test, stage of disease and two-way interaction ApoE x type of test were highly significant (P < 0.0001). Some results were obvious and not surprising (e.g. that results of patients with 4-th stage were much worse than the results of patients with stage 3-rd). It turned out that the best results were obtained by our patients in naming tests, the worst--in learning test with distraction. Patients with ApoE epsilon 4 performed better than patients with none ApoE epsilon 4 in the Rey's test, in the similarity test and in the test which required repeating numbers starting from the last one. The differences between the subgroups of patients with different ApoE alleles were confirmed by different distributions of correlations. All statistical analyses were repeated for more homogenous group of patients (only with stage 3-rd). The pattern of results resembled the previous one (i.e. better performance in the same tests) with one exception: additionally, in delayed recall test patients with none ApoE epsilon 4 performed much better that ApoE epsilon 4. Our results showed that some cognitive processes depended on ApoE genotype. Patients with none ApoE epsilon 4 genotype had less severe deficits in delayed recall of new information. On the other hand, working memory appeared to be less affected in patients with ApoE epsilon 4 genotype. Independent of genotype, both group showed similar impairment of learning ability without deficits in remote memory.     

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).     

The apolipoprotein E epsilon4 allele and incident Alzheimer's disease in persons with mild cognitive impairment

Possession of one or more copies of the apolipoprotein E (APOE) epsilon4 allele is a known risk factor for Alzheimer's disease (AD), but it is uncertain whether the epsilon4 allele is associated with disease incidence among persons with mild cognitive impairment (MCI). We addressed this issue with data from the Religious Orders Study. Participants were 181 older Catholic clergy members who met criteria for MCI based on a uniform structured clinical evaluation; 56 (30.9%) had at least one epsilon4 allele. Clinical evaluations, which included clinical classification of dementia and AD, were repeated annually. During a mean of 5.7 years of observation, 79 persons (43.6%) developed AD. In a proportional hazards model that controlled for age, sex, and education, possession of an epsilon4 allele was associated with a 93% increase in the risk of developing Alzheimer's disease (95% CI; 1.02, 2.63). There was a marginally significant reduction in the effect of epsilon4 in older compared to younger participants (p=.053). The results suggest that possession of an epsilon4 allele does increase risk of AD in persons with MCI.     

Comprehension of lexical ambiguity in healthy aging, mild cognitive impairment, and mild Alzheimer's disease

Two experiments examined processing of lexical ambiguity in healthy older control (HC), mild cognitive impairment (MCI) and Alzheimer's disease (AD) participants. In Experiment 1, groups of HC, MCI and AD participants took part in an ERP study in which they read lexically ambiguous items presented in a subordinate context and primed by the same item presented in a dominant context. Ambiguous items were homonyms (e.g., bank), metaphorical polysemes (e.g., star), or metonyms (e.g., rabbit). All participants exhibited smaller N400s for items preceded by a related prime. In addition, HC participants exhibited a smaller N400 for metonyms than for metaphorical polysemes or homonyms; this effect was diminished in MCI and AD participants. In Experiment 2, HC and MCI participants completed a primed lexical decision task where targets related to the subordinate meaning/sense of ambiguous items were preceded by primes biasing the dominant meaning/sense (e.g., financial-bank-river). In contrast to the results of Experiment 1, both HC and MCI participants showed priming for metonymic items, but not homonyms or metaphorical polysemes. These results suggest that basic knowledge of multiple senses of metonyms is preserved in MCI, but the processing advantage conveyed by this semantic richness is diminished in MCI and AD.     

(1)H-MR spectroscopy differentiates mild cognitive impairment from normal brain aging

This study aimed to characterize the white matter biochemical profile of healthy elderly subjects, mild cognitive impairment (MCI) subjects, and early Alzheimer's disease (AD) patients. We used proton magnetic resonance spectroscopy ((1)H-MRS) to measure myo-inositol, creatine, N-acetylaspartate (NAA) and choline levels from a volume of interest located in the paratrigonal white matter bilaterally. A significantly higher myo-inositol/creatine ratio was found in MCI subjects and AD patients than in controls. The NAA/creatine ratio was reduced in AD patients in the left hemisphere compared to control subjects. The choline/creatine ratio was not significantly different among the three groups. These data suggest that MCI is different from normal brain aging, having a white matter biochemical pattern similar to AD.     

Alzheimer's disease and mild cognitive impairment

As our society ages, age-related diseases assume increasing prominence as both personal and public health concerns. Disorders of cognition are particularly important in both regards, and Alzheimer's disease is by far the most common cause of dementia of aging. In 2000, the prevalence of Alzheimer's disease in the United States was estimated to be 4.5 million individuals, and this number has been projected to increase to 14 million by 2050. Although not an inevitable consequence of aging, these numbers speak to the dramatic scope of its impact. This article focuses on Alzheimer's disease and the milder degrees of cognitive impairment that may precede the clinical diagnosis of probable Alzheimer's disease, such as mild cognitive impairment.     

Aging, mild cognitive impairment, and Alzheimer's disease

Research in the field of aging and dementia is moving forward at a rapid pace, in both basic biology of dementing disorders and clinical investigations. These two approaches to research on aging and dementia need to advance in parallel, such that when work on the pathophysiology of these disorders is translated into therapeutic practice, the appropriately characterized clinical cohorts will be available for therapeutic trials of these treatment strategies.     

Executive function is associated with brain proton magnetic resonance spectroscopy in amnestic mild cognitive impairment

Persons with amnestic mild cognitive impairment (MCI) show deficits on executive function measures, although the neuroanatomic basis of executive function in MCI is unknown. We investigated cognitive correlates of 3-tesla proton magnetic resonance spectroscopy (MRS) of the posterior cingulate gyrus in 26 MCI patients. Posterior cingulate ratio of myo-inositol to creatine (mI/Cr) was negatively correlated (-.51) with spontaneous clock drawing. This relationship was not attenuated after accounting for age, overall cognitive function, or memory performance. This finding suggests a role for the posterior cingulate in executive function in MCI. Proton MRS may offer a means to track neurometabolic changes associated with cognitive impairment in MCI.     

Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer's disease

Abnormally phosphorylated tau accumulates as neurofibrillary tangles and neuropil threads in older persons with and without Alzheimer's disease. The relationship between neurofibrillary tangles and neuropil threads and how they relate to cognitive function is unknown. This study investigated the relationship between phosphorylated tau lesions and cognitive function in 31 persons participating in the Religious Orders Study, a prospective, longitudinal clinicopathological study of aging and Alzheimer's disease. All subjects underwent detailed neuropsychological performance testing within a year of death and evidenced a spectrum of cognitive performance ranging from normal abilities to mild dementia. Measures of neurofibrillary tangle density and phosphorylated tau immunoreactive structures (predominantly neuropil threads) in the entorhinal and perirhinal cortices by quantitative image analysis were significantly correlated (r = 0.5). In multiple linear regression analyses controlling for age, sex, and education, parahippocampal neurofibrillary tangles and neuropil threads were significantly lower in persons without cognitive impairment compared to those with mild cognitive impairment and/or Alzheimer's disease. Further, neurofibrillary tangles were significantly correlated to measures of episodic memory but not other cognitive abilities; neuropil tangles were not significantly related to memory or other cognitive functions. These data indicate that phosphorylated tau pathology in the ventromedial temporal lobe develop prior to the onset of clinical dementia and their presence is associated with cognitive impairment, particularly impairment of episodic memory.     

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.     

Rates of decline distinguish Alzheimer's disease and mild cognitive impairment relative to normal aging: integrating cognition and brain function

AIMS: Increasing age is the strongest risk factor for Alzheimer's disease (AD). Yet, departure from normal age-related decline for established markers of AD including memory, cognitive decline and brain function deficits, has not been quantified. METHODS: We examined the cross-sectional estimates of the "rate of decline" in cognitive performance and psychophysiological measures of brain function over age in AD, preclinical (subjective memory complaint-SMC, Mild Cognitive Impairment-MCI) and healthy groups. Correlations between memory performance and indices of brain function were also conducted. RESULTS: The rate of cognitive decline increased between groups: AD showed advanced decline, and SMC/MCI groups represented intermediate stages of decline relative to normal aging expectations. In AD, advanced EEG alterations (excessive slow-wave/reduced fast-wave EEG, decreased working memory P450 component) were observed over age, which were coupled with memory decline. By contrast, MCI group showed less severe cognitive changes but specific decreases in the working memory N300 component and slow-wave (delta) EEG, associated with decline in memory. DISCUSSION AND INTEGRATIVE SIGNIFICANCE: While the cognitive data suggests a continuum of deterioration associated with increasing symptom severity across groups, integration with brain function measures points to possible distinct compensatory strategies in MCI and AD groups. An integrative approach offers the potential for objective markers of the critical turning point, with age as a potential factor, from mild memory problems to disease.