Atrophy In Mild Cognitive Impairment Research Articles

Hippocampal volume and asymmetry in mild cognitive impairment and Alzheimer's disease: Meta‐analyses of MRI studies

Numerous studies have reported a smaller hippocampal volume in Alzheimer's disease (AD) patients than in aging controls. However, in mild cognitive impairment (MCI), the results are inconsistent. Moreover, the left-right asymmetry of the hippocampus receives less research attention. In this article, meta-analyses are designed to determine the extent of hippocampal atrophy in MCI and AD, and to evaluate the asymmetry pattern of the hippocampal volume in control, MCI, and AD groups. From 14 studies including 365 MCI patients and 382 controls, significant atrophy is found in both the left [Effect size (ES), 0.92; 95% confidence interval (CI), 0.72-1.11] and right (ES, 0.78; 95% CI, 0.57-0.98) hippocampus, which is lower than that in AD (ES, 1.60, 95% CI, 1.37-1.84, in left; ES, 1.52, 95% CI, 1.31-1.72, in right). Comparing with aging controls, the average volume reduction weighted by sample size is 12.9% and 11.1% in left and right hippocampus in MCI, and 24.2% and 23.1% in left and right hippocampus in AD, respectively. The findings show a bilateral hippocampal volume loss in MCI and the extent of atrophy is less than that in AD. By comparing the left and right hippocampal volume, a consistent left-less-than-right asymmetry pattern is found, but with different extents in control (ES, 0.39), MCI (ES, 0.56), and AD (ES, 0.30) group.

Alzheimer Disease: Quantitative Structural Neuroimaging for Detection and Prediction of Clinical and Structural Changes in Mild Cognitive Impairment

To use structural magnetic resonance (MR) images to identify a pattern of regional atrophy characteristic of mild Alzheimer disease (AD) and to investigate whether presence of this pattern prospectively can aid prediction of 1-year clinical decline and increased structural loss in mild cognitive impairment (MCI). The study was conducted with institutional review board approval and compliance with HIPAA regulations. Written informed consent was obtained from each participant. High-throughput volumetric segmentation and cortical surface reconstruction methods were applied to MR images from 84 subjects with mild AD, 175 with MCI, and 139 healthy control (HC) subjects. Stepwise linear discriminant analysis was used to identify regions that best can aid discrimination of HC subjects from subjects with AD. A classifier trained on data from HC subjects and those with AD was applied to data from subjects with MCI to determine whether presence of phenotypic AD atrophy at baseline was predictive of clinical decline and structural loss. Atrophy in mesial and lateral temporal, isthmus cingulate, and orbitofrontal areas aided discrimination of HC subjects from subjects with AD, with fully cross-validated sensitivity of 83% and specificity of 93%. Subjects with MCI who had phenotypic AD atrophy showed significantly greater 1-year clinical decline and structural loss than those who did not and were more likely to have progression to probable AD (annual progression rate of 29% for subjects with MCI who had AD atrophy vs 8% for those who did not). Semiautomated, individually specific quantitative MR imaging methods can be used to identify a pattern of regional atrophy in MCI that is predictive of clinical decline. Such information may aid in prediction of patient prognosis and increase the efficiency of clinical trials.

P1-242: Altered hippocampus functional connectivity in the recognition memory network corrected for grey matter atrophy in mild cognitive impairment

P1-242: Altered hippocampus functional connectivity in the recognition memory network corrected for grey matter atrophy in mild cognitive impairment

O2-05-05: Association of CSF total Tau and phospho-Tau (181) with cerebral atrophy in mild cognitive impairment and Alzheimer's disease

O2-05-05: Association of CSF total Tau and phospho-Tau (181) with cerebral atrophy in mild cognitive impairment and Alzheimer's disease

IC-P2-142: Association of CSF total Tau and phospho-tau (181) with cerebral atrophy in mild cognitive impairment and Alzheimer's disease

Alzheimer’s disease is a hyperphosphorylated form of the microtubulebinding protein tau. Hyperphosphorylation of tau, which occurs significantly within the proline-rich domain, is associated with structural and functional changes that are poorly understood. Understanding the relationship between hyperphosphorylation of tau and structural changes in tau is a central question in the mechanism of neurofibrillary tangle formation. Methods: Peptides and larger protein constructs derived from the proline-rich region of tau as well as other tau domains were synthesized with defined phosphrylation states. The non-phosphorylated and phosphorylated peptides and proteins were analyzed by NMR and circular dichroism in order to identify the specific local changes in the structure of tau that are induced by hyperphosphorylation. Results: Phosphorylation of serine and threonine residues throughout the proline-rich domain of tau induced structural changes from a disordered conformation to a type II polyproline helix. The largest phosphorylation-induced structural changes were observed in tau peptides derived from residues 174-183 or residues 229-238. Phosphorylation-induced changes to polyproline helix were also observed in tau peptides incorporating residues 211-219. Phosphorylation of tau peptides derived from tau residues 196-209 resulted in the disruption of a nascent -helix. In these peptides, phosphoserine and phosphothreonine residues exhibited ordered values of phi ( ) (3J N 3.1-6.2 Hz; mean 4.7 Hz) compared to non-phosphorylated serine and threonine, indicating specific conformational restriction upon phosphorylation. Phosphorylation within the proline-rich domain did not affect the cis-trans isomerization equilibrium of the peptides examined, suggesting that phosphorylation-associated cis-trans isomerism is due to long-range interactions. As the proline-rich domains are linker regions between hydrophobic and aggregation-prone domains of tau, these results suggest that global reorganization of tau may occur upon hyperphosphorylation of proline-rich domain in tau. These results provide insight into possible mechanisms of phosphorylation-dependent structural changes of tau in Alzheimer’s disease. Conclusions: Hyperphosphorylation within the proline-rich domain of tau can induce specific local structural changes from a disordered conformation to an ordered polyproline II helix conformation.

IC-P3-223: Automated longitudinal 3D mapping of hippocampal ADASCPG delayed recall effects in 293 normal elderly, MCI and AD subjects

Background: The Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAScog) is a primary outcome measure in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) clinical trials. Hippocampal atrophy has recently been proposed as a sensitive biomarker in AD and MCI. Methods: We applied a previously validated automated machine learning algorithm based on adaptive boosting (Morra et al., 2008) to segment the hippocampi in baseline and 12-month follow-up 3D T1-weighted brain MRIs of 109 cognitively normal elderly (NC), 133 MCI and 51 AD subjects from the ADNI study. We then applied the radial distance atrophy mapping approach to examine in 3D the structural hippocampal correlates of ADAScog delayed recall (ADAScog-DR). 3D statistical maps were corrected for multiple comparisons using permutation testing thresholded at p 0.01. Results: The groups were well balanced with regard to age, race and education. The MCI group had significantly more men (71%) relative to the NC (52%) and the AD group (51%). The MCI and AD groups showed a significant decline in ADAScog-DR over 12 months (MCI 0.42, p 0.012; AD 0.49, p 0.005). At baseline ADAScog-DR showed significant correlations with atrophy of CA1 and subicular hippocampal subregions in MCI (r 0.2-0.3, left pcorrected 0.03; right pcorrected 0.04) and the right mid/posterior CA1, CA2-3 and subiculum in AD (r 0.35-0.55, pcorrected 0.0004). At followup, ADAScog-DR correlated with atrophy of the left more then right CA1 and subiculum in MCI (r 0.2-0.3, pcorrected 0.003) and the right anterior CA1 and subiculum in AD (r 0.25-0.45; pcorrected 0.017). Correlations between baseline ADAScog-DR and posterior right hippocampal atrophy were observed at trend level in NC (r 0.2-0.4; pcorrected 0.07). Correlations with the global ADAScog ratings (ADAScog11 and ADAScog-modified) were generally less significant than those observed with ADAScog-DR. Conclusions: We demonstrated regionally specific correlations between ADAScog-DR and hippocampal atrophy in MCI and AD. The MCI 3D maps revealed correlations with hippocampal subregions known to be affected early in MCI. Our high throughput automated segmentation approach is a promising technique for analyzing large epidemiological and clinical trial datasets. IC-P3-224 REGIONAL VARIATIONS IN AGE DEPENDENCE OF P-GP MEDIATED TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER MEASURED USING (R)[C]VERAPAMIL AND POSITRON EMISSION TOMOGRAPHY

Spatial patterns of brain atrophy in MCI patients, identified via high-dimensional pattern classification, predict subsequent cognitive decline

Spatial patterns of brain atrophy in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) were measured via methods of computational neuroanatomy. These patterns were spatially complex and involved many brain regions. In addition to the hippocampus and the medial temporal lobe gray matter, a number of other regions displayed significant atrophy, including orbitofrontal and medial-prefrontal grey matter, cingulate (mainly posterior), insula, uncus, and temporal lobe white matter. Approximately 2/3 of the MCI group presented patterns of atrophy that overlapped with AD, whereas the remaining 1/3 overlapped with cognitively normal individuals, thereby indicating that some, but not all, MCI patients have significant and extensive brain atrophy in this cohort of MCI patients. Importantly, the group with AD-like patterns presented much higher rate of MMSE decline in follow-up visits; conversely, pattern classification provided relatively high classification accuracy (87%) of the individuals that presented relatively higher MMSE decline within a year from baseline. High-dimensional pattern classification, a nonlinear multivariate analysis, provided measures of structural abnormality that can potentially be useful for individual patient classification, as well as for predicting progression and examining multivariate relationships in group analyses.

Baseline predictors of rates of hippocampal atrophy in mild cognitive impairment

A large cohort of subjects with mild cognitive impairment (MCI) was categorized into tertiles based on hippocampal atrophy rates, as a proxy for Alzheimer-type pathology. We compared baseline clinical, neuropsychological, and MRI measures to characterize these MCI subgroups. Serial MRI data of 323 subjects with MCI (49% men; mean +/- SD age: 69 +/- 9 years), followed for 2 years in a clinical trial, were available. Baseline hippocampal and whole brain volumes (WBV) were measured, and hippocampal volume change was assessed. Baseline medial temporal lobe atrophy (MTA), white matter hyperintensities (WMH), and lacunes were rated visually. The cohort was categorized into tertiles based on hippocampal atrophy rates (absent, moderate, and severe). Rates of hippocampal atrophy (%/year) were 0.0 +/- 0.8 in the absent, 1.7 +/- 0.4 in the moderate, and 3.6 +/- 1.0 in the severe (mean +/- SD) tertile. Older age and the APOE epsilon 4 allele were associated with higher hippocampal atrophy rates (p < 0.0001 and p = 0.015). General cognition deteriorated over the MCI groups (p < 0.0001), whereas, after adjustment for age and sex, episodic memory and executive function did not. Baseline hippocampal atrophy was associated with increasing atrophy rates (hippocampal volume: p = 0.025; MTA score: p = 0.008); in contrast, WBV, WMH, and lacunes, adjusted for age and sex, were not significantly associated with hippocampal atrophy rates. In mild cognitive impairment (MCI), older age, poorer general cognition, hippocampal atrophy, and APOE epsilon 4 predict subsequent accelerated rates of hippocampal atrophy, suggestive of the accumulation of Alzheimer-type pathology, which may become clinically manifest in the future. These markers may improve identification of subjects with MCI at risk for Alzheimer disease.

P-063: Baseline predictors of rates of hippocampal atrophy in mild cognitive impairment: A longitudinal study

P-063: Baseline predictors of rates of hippocampal atrophy in mild cognitive impairment: A longitudinal study

Hippocampal and entorhinal atrophy in mild cognitive impairment

To evaluate the utility of MRI hippocampal and entorhinal cortex atrophy in predicting conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). Baseline brain MRI was performed in 139 patients with MCI, broadly defined, and 63 healthy controls followed for an average of 5 years (range 1 to 9 years). Hippocampal and entorhinal cortex volumes were each largest in controls, intermediate in MCI nonconverters, and smallest in MCI converters to AD (37 of 139 patients converted to AD). In separate Cox proportional hazards models, covarying for intracranial volume, smaller hippocampal volume (risk ratio [RR] 3.62, 95% CI 1.93 to 6.80, p < 0.0001), and entorhinal cortex volume (RR 2.43, 95% CI 1.56 to 3.79, p < 0.0001) each predicted time to conversion to AD. Similar results were obtained for hippocampal and entorhinal cortex volume in patients with MCI with Mini-Mental State Examination (MMSE) scores > or = 27 out of 30 (21% converted to AD) and in the subset of patients with amnestic MCI (35% converted to AD). In the total patient sample, when both hippocampal and entorhinal volume were entered into an age-stratified Cox model with sex, MMSE, education, and intracranial volume, smaller hippocampal volume (RR 2.21, 95% CI 1.14 to 4.29, p < 0.02) and entorhinal cortex volume (RR 2.48, 95% CI 1.54 to 3.97, p < 0.0002) predicted time to conversion to AD. Similar results were obtained in a Cox model that also included Selective Reminding Test (SRT) delayed recall and Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Symbol as predictors. Based on logistic regression models in the 3-year follow-up sample, for a fixed specificity of 80%, the sensitivities for MCI conversion to AD were as follows: age 43.3%, MMSE 43.3%, age + MMSE 63.7%, age + MMSE + SRT delayed recall + WAIS-R Digit Symbol 80.6% (79.6% correctly classified), hippocampus + entorhinal cortex 66.7%, age + MMSE + hippocampus + entorhinal cortex 76.7% (85% correctly classified), age + MMSE + SRT delayed recall + WAIS-R Digit Symbol + hippocampus + entorhinal cortex 83.3% (86.8% correctly classified). Smaller hippocampal and entorhinal cortex volumes each contribute to the prediction of conversion to Alzheimer disease. Age and cognitive variables also contribute to prediction, and the added value of hippocampal and entorhinal cortex volumes is small. Nonetheless, combining these MRI volumes with age and cognitive measures leads to high levels of predictive accuracy that may have potential clinical application.

Increased fMRI responses during encoding in mild cognitive impairment

Structural and functional magnetic resonance imaging (fMRI) was performed on 21 healthy elderly controls, 14 subjects with mild cognitive impairment (MCI) and 15 patients with mild Alzheimer's disease (AD) to investigate changes in fMRI activation in relation to underlying structural atrophy. The fMRI paradigm consisted of associative encoding of novel picture-word pairs. Structural analysis of the brain was performed using voxel-based morphometry (VBM) and hippocampal volumetry. Compared to controls, the MCI subjects exhibited increased fMRI responses in the posterior hippocampal, parahippocampal and fusiform regions, while VBM revealed more atrophy in MCI in the anterior parts of the left hippocampus. Furthermore, the hippocampal volume and parahippocampal activation were negatively correlated in MCI, but not in controls or in AD. We suggest that the increased fMRI activation in MCI in the posterior medial temporal and closely connected fusiform regions is compensatory due to the incipient atrophy in the anterior medial temporal lobe.

Three-dimensional Patterns of Hippocampal Atrophy in Mild Cognitive Impairment

To measure hippocampal volumes in patients diagnosed as having subtypes of mild cognitive impairment (MCI) relative to those of elderly control subjects and those of patients with Alzheimer disease (AD) using 3-dimensional mesh reconstructions. A magnetic resonance imaging volumetric study of MCI subgroups (MCI, amnesic subtype [MCI-A]; and MCI, multiple cognitive domain subtype) using 3-dimensional mesh reconstructions of the structure. Referral dementia clinic. Twenty-six subjects with MCI (MCI-A, n = 6; and MCI, multiple cognitive domain subtype, n = 20), 20 subjects with AD, and 20 controls who were equivalent in age, education, and sex distributions. Three-dimensional parametric mesh models of the hippocampus and total hippocampal volumes. The hippocampi of the patients with AD were significantly atrophic relative to those of the healthy controls. The MCI, multiple cognitive domain subtype, group did not differ from the controls, yet was significantly different from the MCI-A and the AD groups. The MCI-A patients had significant hippocampal atrophy compared with the controls, and did not differ significantly from the patients with AD. These data add to the growing evidence that there are multiple forms of MCI, that they have distinct neuropathological correlates, and that MCI, multiple cognitive domain subtype, is not a more advanced form of the MCI-A subtype.

Morphometric MRI study of hippocampal shape in MCI using spherical harmonics

Background: Mild cognitive impairment (MCI) is characterized by memory complaints and impairment in the absence of dementia and confers a high risk for AD. Identifying medial temporal morphological abnormalities, in circuits required for learning and memory, may be critical for early diagnosis and treatment of MCI and AD. Objective: Volumetric analysis can identify hippocampal atrophy in MCI, but does not localize the structural changes. Shape analysis has the potential to provide important information beyond volume and may localize regionally specific structural changes in the absence of volume differences. This study performed hippocampal shape analysis aiming at a global and local quantitative representation of shape changes in MCI. Methods: Participants were 40 adults with amnestic MCI (age 72.5 3.3), 40 adults with cognitive complaints (CC) but no impairment (72.6 2.6), and 42 normal controls (CN) (70.8 2.6). MRI data were a T1-weighted SPGR coronal series acquired on a GE 1.5T LX magnet. The hippocampi were segmented using BRAINS software. The left and right hippocampi were treated as a single shape configuration. The spherical harmonics (SPHARM) description was used for surface modeling, with the parameter space being aligned according to the first order ellipsoid for surface correspondence. After normalizing for the total volume, landmarks were created by uniform surface sampling (Figure 1(a,b)) and aligned by a quaternion-based algorithm. For each landmark, the local shape change was defined as the distance between an individual and the mean along the normal direction of the mean surface. Surface signals were modeled as Gaussian random fields. Heat kernel smoothing was employed to increase SNR on the hippocampal surface (Figure 1(c)) and statistical inference was performed via random fields theory. Conclusions: The results of group analyses (t-maps in Figure 2) show that statistically significant regions of shape changes only appear between CN and MCI. The CC group showed a more intermediate pattern. The structural changes in MCI were primarily located in the anterior right hippocampus and posterior left hippocampus (Figure 3). Shape analysis has the potential to inform early detection and is likely to be useful for longitudinal monitoring of response to therapeutic agents. P-121 RESTING FDG-PET IN NEUROLOGICALLY NORMAL INDIVIDUALS REPORTING DREAM ENACTMENT BEHAVIOR: PRECLINICAL DEMENTIA WITH LEWY BODIES?

A voxel based morphometry study on mild cognitive impairment

Background: Mild cognitive impairment (MCI) is the most widely used concept in classifying cognitive impairment in the elderly who do not fulfil the criteria for dementia. MCI is considered to...

Structural imaging in cognitive impairment and the dementias: an update.

The purpose of this review is to explore and summarize recent advances in the structural imaging of cognitive impairment and the dementias. The focus is practical, covering issues that bear relevance to clinical practice or diagnosis. Findings in mild cognitive impairment, a state preceding but not necessarily leading to dementia, are discussed. Data from dementias other than Alzheimer's disease are reviewed at some length before outlining some novel issues in Alzheimer's disease imaging. A number of studies have proposed some medial temporal atrophy in mild cognitive impairment, and this may have some clinical value in predicting conversion to dementia. Data on other regions have also been proposed to predict conversion, but a number of studies on these regions have yielded entirely conflicting results. Data are also accumulating on the medial temporal lobe and other regions in non-Alzheimer's dementias. The medial temporal lobe is still the region of interest when studying mild cognitive impairment and Alzheimer's disease. Medial temporal atrophy, or lack thereof, may be of some diagnostic value even in non-Alzheimer's dementias. Medial temporal atrophy, however, is not an Alzheimer's disease-specific feature. One potential approach to improve the radiological diagnosis of dementia is mapping a number of regions in order to define patterns of atrophy. At present, however, the scarcity of existing data prevents unambiguous conclusions on this issue.

Hippocampal atrophy in mild cognitive impairment. A population-based study

Hippocampal atrophy in mild cognitive impairment. A population-based study