Prognostic value of Alzheimer's biomarkers in mild cognitive impairment: the effect of age at onset.

OBJECTIVE: The aim of this study is to assess the impact of age at onset on the prognostic value of Alzheimer's biomarkers in a large sample of patients with mild cognitive impairment (MCI). METHODS: We measured Aß42, t-tau, hippocampal volume on magnetic resonance imaging (MRI) and cortical metabolism on fluorodeoxyglucose-positron emission tomography (FDG-PET) in 188 MCI patients followed for at least 1 year. We categorised patients into earlier and later onset (EO/LO). Receiver operating characteristic curves and corresponding areas under the curve (AUCs) were performed to assess and compar the biomarker prognostic performances in EO and LO groups. Linear Model was adopted for estimating the time-to-progression in relation with earlier/later onset MCI groups and biomarkers. RESULTS: In earlier onset patients, all the assessed biomarkers were able to predict cognitive decline (p < 0.05), with FDG-PET showing the best performance. In later onset patients, all biomarkers but t-tau predicted cognitive decline (p < 0.05). Moreover, FDG-PET alone in earlier onset patients showed a higher prognostic value than the one resulting from the combination of all the biomarkers in later onset patients (earlier onset AUC 0.935 vs later onset AUC 0.753, p < 0.001). Finally, FDG-PET showed a different prognostic value between earlier and later onset patients (p = 0.040) in time-to-progression allowing an estimate of the time free from disease. DISCUSSION: FDG-PET may represent the most universal tool for the establishment of a prognosis in MCI patients and may be used for obtaining an onset-related estimate of the time free from disease.

Prediction of AD dementia by biomarkers following the NIA-AA and IWG diagnostic criteria in MCI patients from three European memory clinics.

INTRODUCTION: Proposed diagnostic criteria (international working group and National Institute on Aging and Alzheimer's Association) for Alzheimer's disease (AD) include markers of amyloidosis (abnormal cerebrospinal fluid [CSF] amyloid beta [Aß]42) and neurodegeneration (hippocampal atrophy, temporo-parietal hypometabolism on [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET), and abnormal CSF tau). We aim to compare the accuracy of these biomarkers, individually and in combination, in predicting AD among mild cognitive impairment (MCI) patients. METHODS: In 73 MCI patients, followed to ascertain AD progression, markers were measured. Sensitivity and specificity, positive (LR+) and negative (LR-) likelihood ratios, and crude and adjusted hazard ratios were computed. RESULTS: Twenty-nine MCI patients progressed and 44 remained stable. Positivity to any marker achieved the lowest LR- (0.0), whereas the combination Aß42 plus FDG-PET achieved the highest LR+ (6.45). In a survival analysis, positivity to any marker was associated with 100% conversion rate, whereas negativity to all markers was associated with 100% stability. DISCUSSION: The best criteria combined amyloidosis and neurodegeneration biomarkers, whereas the individual biomarker with the best performance was FDG-PET.

Mild cognitive impairment with suspected nonamyloid pathology (SNAP): Prediction of progression.

OBJECTIVES: The aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non-Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI). METHODS: We measured markers of amyloid pathology (CSF ß-amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [(18)F]-fluorodeoxyglucose-PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A+/A- and N+/N- based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A-N+ cases. RESULTS: The proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71% (60/85) in A-N-, A+N-, SNAP, and A+N+, respectively; the proportion of APOE ε4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A+N- and A+N+ groups (p ≤ 0.005). Hypometabolism in SNAP patients was comparable to A+N+ patients (p = 0.154), while hippocampal atrophy was more severe in SNAP patients (p = 0.002). Compared with A-N-, SNAP and A+N+ patients had significant risk of progressive cognitive deterioration (hazard ratio = 2.7 and 3.8, p = 0.016 and p < 0.001), while A+N- patients did not (hazard ratio = 1.13, p = 0.771). In A+N- and A+N+ groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism (r = 0.42, p = 0.073). CONCLUSIONS: Our findings support the notion that patients with SNAP MCI feature a specific risk progression profile.

Occipital sources of resting-state alpha rhythms are related to local gray matter density in subjects with amnesic mild cognitive impairment and Alzheimer's disease.

Occipital sources of resting-state electroencephalographic (EEG) alpha rhythms are abnormal, at the group level, in patients with amnesic mild cognitive impairment (MCI) and Alzheimer's disease (AD). Here, we evaluated the hypothesis that amplitude of these occipital sources is related to neurodegeneration in occipital lobe as measured by magnetic resonance imaging. Resting-state eyes-closed EEG rhythms were recorded in 45 healthy elderly (Nold), 100 MCI, and 90 AD subjects. Neurodegeneration of occipital lobe was indexed by weighted averages of gray matter density, estimated from structural MRIs. EEG rhythms of interest were alpha 1 (8-10.5 Hz) and alpha 2 (10.5-13 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography. Results showed a positive correlation between occipital gray matter density and amplitude of occipital alpha 1 sources in Nold, MCI, and AD subjects as a whole group (r = 0.3, p = 0.000004, N = 235). Furthermore, there was a positive correlation between the amplitude of occipital alpha 1 sources and cognitive status as revealed by Mini Mental State Examination score across all subjects (r = 0.38, p = 0.000001, N = 235). Finally, amplitude of occipital alpha 1 sources allowed a moderate classification of individual Nold and AD subjects (sensitivity: 87.8%; specificity: 66.7%; area under the receiver operating characteristic curve: 0.81). These results suggest that the amplitude of occipital sources of resting-state alpha rhythms is related to AD neurodegeneration in occipital lobe along pathologic aging.

Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI.

BACKGROUND: The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). METHODS: Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid Aß1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms. RESULTS: Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency. CONCLUSION: These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials.

Hippocampal and amygdalar local structural differences in elderly patients with schizophrenia.

OBJECTIVES: Morphological abnormalities have been reported for the hippocampi and amygdalae in young schizophrenia patients, but very little is known about the pattern of abnormalities in elderly schizophrenia patients. Here we investigated local structural differences in the hippocampi and amygdalae of elderly schizophrenia patients compared with healthy elderly subjects. We also related these differences to clinical symptom severity. DESIGN: 20 schizophrenia patients (mean age: 67.4 ± 6.2 years; Mini-Mental State Exam: 22.8 ± 4.4) and 20 healthy elderly subjects (70.3 ± 7.5 years; 29.0 ± 1.1) underwent high resolution magnetic resonance imaging of the brain. The Radial Atrophy Mapping technique was used to reconstruct the 3D shape of the amygdala and the hippocampus. Local differences in tissue reductions were computed between groups and permutation tests were run to correct for multiple comparisons, in statistical maps thresholded at p = 0.05. RESULTS: Significant tissue reduction was observed bilaterally in the amygdala and hippocampus of schizophrenia patients. The basolateral-ventral-medial amygdalar nucleus showed the greatest involvement, with over 30% local tissue reduction. The centro-medial, cortical, and lateral nuclei were also atrophic in patients. The hippocampus showed significant tissue loss in the medio-caudal and antero-lateral aspects of CA1, and in medial section of its left head (pre- and para-subiculum). In the left amygdala and hippocampus, local tissue volumes were significantly correlated with negative symptoms. CONCLUSIONS: Tissue loss and altered morphology were found in elderly schizophrenia patients. Tissue loss mapped to amygdalo-hippocampal subregions known to have bidirectional and specific connections with frontal cortical and limbic structures and was related to clinical severity.

A standardized [18F]-FDG-PET template for spatial normalization in statistical parametric mapping of dementia.

[18F]-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) is a widely used diagnostic tool that can detect and quantify pathophysiology, as assessed through changes in cerebral glucose metabolism. [18F]-FDG PET scans can be analyzed using voxel-based statistical methods such as Statistical Parametric Mapping (SPM) that provide statistical maps of brain abnormalities in single patients. In order to perform SPM, a "spatial normalization" of an individual's PET scan is required to match a reference PET template. The PET template currently used for SPM normalization is based on [15O]-H2O images and does not resemble either the specific metabolic features of [18F]-FDG brain scans or the specific morphological characteristics of individual brains affected by neurodegeneration. Thus, our aim was to create a new [18F]-FDG PET aging and dementia-specific template for spatial normalization, based on images derived from both age-matched controls and patients. We hypothesized that this template would increase spatial normalization accuracy and thereby preserve crucial information for research and diagnostic purposes. We investigated the statistical sensitivity and registration accuracy of normalization procedures based on the standard and new template-at the single-subject and group level-independently for subjects with Mild Cognitive Impairment (MCI), probable Alzheimer's Disease (AD), Frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB). We found a significant statistical effect of the population-specific FDG template-based normalisation in key anatomical regions for each dementia subtype, suggesting that spatial normalization with the new template provides more accurate estimates of metabolic abnormalities for single-subject and group analysis, and therefore, a more effective diagnostic measure.

Increase of theta frequency is associated with reduction in regional cerebral blood flow only in subjects with mild cognitive impairment with higher upper alpha/low alpha EEG frequency power ratio.

BACKGROUND: Several biomarkers have been proposed for detecting Alzheimer's disease (AD) in its earliest stages, that is, in the predementia stage. In an attempt to find noninvasive biomarkers, researchers have investigated the feasibility of neuroimaging tools, such as MRI, SPECT as well as neurophysiological measurements using EEG. Moreover, the increase of EEG alpha3/alpha2 frequency power ratio has been associated with AD-converters subjects with mild cognitive impairment (MCI). OBJECTIVE: To study the association of alpha3/alpha2 frequency power ratio with regional cerebral blood flow (rCBF) changes in subjects with MCI. METHODS: Twenty-seven adult subjects with MCI underwent EEG recording and perfusion single-photon emission computed tomography (SPECT) evaluation. The alpha3/alpha2 frequency power ratio was computed for each subject. Two groups were obtained according to the median values of alpha3/alpha2, at a cut-off of 1.17. Correlation between brain perfusion and EEG markers were detected. RESULTS: Subjects with higher alpha3/alpha2 frequency power ratio showed a constant trend to a lower perfusion than low alpha3/alpha2 group. The two groups were significantly different as about the hippocampal volume and correlation with the theta frequency activity. CONCLUSION: There is a complex interplay between cerebral blood flow, theta frequency activity, and hippocampal volume in MCI patients with prodromal Alzheimer's disease, characterized by higher EEG alpha3/alpha2 frequency power ratio.

The in vivo topography of cortical changes in healthy aging and prodromal Alzheimer's disease.

BACKGROUND: Gray matter atrophy is regarded as a valid marker of neurodegeneration in Alzheimer's disease (AD), but few studies have investigated in detail the topographic changes associated with normal aging. In addition, few studies have compared the changes in the earliest clinical stage of AD (prodromal AD (pAD)) with those of healthy aging. Here we aimed to investigate the topographical distribution of age-related cortical atrophy and to compare it with that associated with prodromal and estabilished AD. METHODS: Structural T1-weighted high-resolution brain magnetic resonance imaging scans were acquired from 60 healthy volunteers (20 young adults, YA: age 32.7 +/- 4.5 years; 40 elderly subjects, HE: age 71.3 +/- 6.2 years), 16 mild cognitive impairment subjects who converted to AD within 2 years (prodromal AD, pAD: age 72.8 +/- 5.4), and 20 mild to moderate AD patients (mAD, age 72.5 +/- 10.3). Cortical gray matter differences were investigated using a surface-based anatomical mesh modeling technique (cortical pattern matching) and region-of-interest (ROI) analyses based on hypothesized brain networks taught to have a functional and a structural link to each other. Differences in cortical atrophy were assessed between groups, as well as the effect of age within groups. RESULTS: HE compared to YA showed a 10-30% deficit in cortical gray matter in widespread frontal, temporal, and parietal regions (p = 0.0001 by permutation testing), 6-13% loss in the visual and sensorimotor cortices (p < 0.01) and up to 13% loss in the direct hippocampal pathway ROIs (p < 0.001). pAD patients showed on average 8-9% cortical loss compared to HE (p < 0.0001), mainly in the left (up to 6% loss, p = 0.06) and right polysynaptic hippocampal pathway ROIs (up to 8% loss, p = 0.01), and in the left and right olfactory/orbitofrontal cortex (up to 12-15% loss, p < 0.001). The pattern of cortical atrophy in mAD versus HE was similar to that in pAD, but was more severe in the direct hippocampal pathway ROIs and sensorimotor, visual and temporal cortices (13-15% loss compared with HE, p < 0.0001). CONCLUSION: Gray matter loss occurs during aging with rates of atrophy even more severe than that observed during the course of AD. These changes may be caused by normal mechanisms. In pAD, cortical atrophy due to disease is milder than that due to aging, maybe resulting from a slowed down velocity of cell loss, but affects specific brain areas. These findings are consistent with the view that AD is not merely accelerated aging.

Prediction of dementia in MCI patients based on core diagnostic markers for Alzheimer disease.

OBJECTIVES: The current model of Alzheimer disease (AD) stipulates that brain amyloidosis biomarkers turn abnormal earliest, followed by cortical hypometabolism, and finally brain atrophy ones. The aim of this study is to provide clinical evidence of the model in patients with mild cognitive impairment (MCI). METHODS: A total of 73 patients with MCI from 3 European memory clinics were included. Brain amyloidosis was assessed by CSF Aß42 concentration, cortical metabolism by an index of temporoparietal hypometabolism on FDG-PET, and brain atrophy by automated hippocampal volume. Patients were divided into groups based on biomarker positivity: 1) Aß42- FDG-PET- Hippo-, 2) Aß42+ FDG-PET- Hippo-, 3) Aß42 + FDG-PET + Hippo-, 4) Aß42 + FDG-PET+ Hippo+, and 5) any other combination not in line with the model. Measures of validity were prevalence of group 5, increasing incidence of progression to dementia with increasing biological severity, and decreasing conversion time. RESULTS: When patients with MCI underwent clinical follow-up, 29 progressed to dementia, while 44 remained stable. A total of 26% of patients were in group 5. Incident dementia was increasing with greater biological severity in groups 1 to 5 from 4% to 27%, 64%, and 100% (p for trend < 0.0001), and occurred increasingly earlier (p for trend = 0.024). CONCLUSIONS: The core biomarker pattern is in line with the current pathophysiologic model of AD. Fully normal and fully abnormal pattern is associated with exceptional and universal development of dementia. Cases not in line might be due to atypical neurobiology or inaccurate thresholds for biomarker (ab)normality.

Diagnostic accuracy of markers for prodromal Alzheimer's disease in independent clinical series.

OBJECTIVE: To capitalize on data from different clinical series to compare sensitivity and specificity of individual biomarkers for predicting mild cognitive impairment (MCI) progression to Alzheimer's disease (AD). METHODS: Medial temporal atrophy, cortical hypometabolism, and cerebrospinal fluid biomarkers were assessed in 18 patients with mild cognitive impairment (MCI) with prodromal AD (pAD; conversion time, 26 ± 12 months) and 18 stable MCI (sMCI) patients from the Translational Outpatient Memory Clinic cohort, as well as in 24 pAD patients (conversion time, 36 ± 12 months) and 33 sMCI patients from the Alzheimer's Disease Neuroimaging Initiative cohort. Medial temporal atrophy was measured by manual, semi-automated, and automated hippocampal volumetry; cortical hypometabolism was measured using several indices of AD-related hypometabolism pattern; and cerebrospinal fluid markers were amyloid ß (Aß)42 and total tau protein concentrations. For each biomarker, sensitivity for pAD, specificity for sMCI, and diagnostic accuracy were computed. RESULTS: Sensitivity to predict MCI conversion to AD in the Alzheimer's Disease Neuroimaging Initiative and Translational Outpatient Memory Clinic cohorts was 79% and 94% based on Aß42, 46% and 28% based on hippocampal volumes, 33% to 66% and 56% to 78% based on different hypometabolism indices, and 46% and 61% based on total tau levels, respectively. Specificity to exclude sMCI was 27% and 50% based on Aß42, 76% and 94% based on hippocampal volumes, 58% to 67% and 55% to 83% based on different hypometabolism indices, and 61% and 83% based on total tau levels, respectively. CONCLUSIONS: Current findings suggest that Aß42 concentrations and hippocampal volumes may be used in combination to best identify pAD.

Distinct cerebrospinal fluid amyloid-beta peptide signatures in cognitive decline associated with Alzheimer's disease and schizophrenia.

Mild alterations in cognitive function are present in normal aging and severe cognitive alterations are a hallmark of Alzheimer's disease (AD). Cognitive deficits are prevalent in patients with schizophrenia (SCZ) and worsen with old age. We recently reported that elderly SCZ patients show reduced levels of amyloid-beta (Aß)1-42 in cerebrospinal fluid (CSF). To further clarify the role of Aß in cognitive decline, we analyzed the whole panel of CSF Aß isoforms in elderly SCZ patients as well as in sporadic AD using SELDI TOF MS. The immunoproteomic study revealed, in all analyzed CSF samples, the presence of 15 different Aß peptides. In CSF from SCZ, we detected an overall strong reduction of almost all Aß species while in sporadic AD Aß1-42 was the only peptide reduced. A significant independent association between Aß1-40 levels and global cognition was found in SCZ. In addition, in SCZ patients, duration of therapy was positively associated with soluble amyloid precursor protein alpha levels, the total amount of CSF Aß and the most abundant Aß1-40 isoform. These data suggests a dysmetabolism of amyloid precursor protein in older SCZ patients. Thus, the quite comparable reduction of CSF Aß1-42 in AD and in elderly SCZ patients reflects different pathophysiological dynamics in ageing brain.

Summary metrics to assess Alzheimer disease-related hypometabolic pattern with 18F-FDG PET: head-to-head comparison.

UNLABELLED: In the recently revised diagnostic criteria for Alzheimer disease (AD), the National Institute on Aging and Alzheimer Association suggested that confidence in diagnosing dementia due to AD and mild cognitive impairment (MCI) due to AD could be improved by the use of certain biomarkers, such as (18)F-FDG PET evidence of hypometabolism in AD-affected brain regions. Three groups have developed automated data analysis techniques to characterize the AD-related pattern of hypometabolism in a single measurement. In this study, we sought to directly compare the ability of these three (18)F-FDG PET data analysis techniques--the PMOD Alzheimer discrimination analysis tool, the hypometabolic convergence index, and a set of meta-analytically derived regions of interest reflecting AD hypometabolism pattern (metaROI)--to distinguish moderate or mild AD dementia patients and MCI patients who subsequently converted to AD dementia from cognitively normal older adults. METHODS: One hundred sixty-six (18)F-FDG PET patients from the AD Neuroimaging Initiative, 308 from the Network for Efficiency and Standardization of Dementia Diagnosis, and 176 from the European Alzheimer Disease Consortium PET study were categorized, with masking of group classification, as AD, MCI, or healthy control. For each AD-related (18)F-FDG PET index, receiver-operating-characteristic curves were used to characterize and compare subject group classifications. RESULTS: The 3 techniques were roughly comparable in their ability to distinguish each of the clinical groups from cognitively normal older adults with high sensitivity and specificity. Accuracy of classification (in terms of area under the curve) in each clinical group varied more as a function of dataset than by technique. All techniques were differentially sensitive to disease severity, with the classification accuracy for MCI due to AD to moderate AD varying from 0.800 to 0.949 (PMOD Alzheimer tool), from 0.774 to 0.967 (metaROI), and from 0.801 to 0.983 (hypometabolic convergence index). CONCLUSION: The 3 tested techniques have the potential to help detect AD in research and clinical settings. Additional efforts are needed to clarify their ability to address particular scientific and clinical questions. Their incremental diagnostic value over other imaging and biologic markers makes them easier to implement by other groups for these purposes.

Hippocampal and amygdalar volume changes in elderly patients with Alzheimer's disease and schizophrenia.

Patients with Alzheimer's disease (AD) and schizophrenia display cognitive, behavioural disturbances and morphological abnormalities. Although these latter reflect progressive neurodegeneration in AD, their significance in schizophrenia is still unclear. We explored the patterns of hippocampal and amygdalar atrophy in those patients and their associations with clinical parameters. Structural magnetic resonance imaging was performed in 20 elderly schizophrenia patients, 20 AD and 19 healthy older controls. Hippocampal and amygdalar volumes were obtained by manual segmentation with a standardized protocol and compared among groups. In both schizophrenia and AD patients, left hippocampal and amygdalar volumes were significantly smaller. The hippocampus/amygdala ratio was significantly lower in schizophrenia compared to both AD cases [2.4 bilaterally, 95% C.I. 2.2 to 2.7] and healthy controls bilaterally [2.5, 95% C.I. 2.3 to 2.9 in left and 2.7, 95% C.I. 2.4 to 3.1 in right hemisphere]. In schizophrenia patients, a significant positive correlation was found between age at disease onset and the right hippocampus/amygdala volume ratio (Spearman rho=0.56). Negative symptoms correlated with higher right/left amygdala volume ratio (Spearman's rho=0.43). Our data show that unlike AD, the hippocampus/amygdala ratio is abnormally low and correlates with the age at onset in schizophrenia, being a neurodevelopmental signature of the disease.

Alzheimer's CSF markers in older schizophrenia patients.

OBJECTIVES: Cognitive impairment is prevalent in older schizophrenia patients but its biological basis is unknown. Neuropathological studies have not revealed Alzheimer disease (AD) lesion burden but in vivo data are lacking. METHOD: We investigated the concentrations of CSF biomarkers of brain amyloidosis (Abeta42) and neurodegeneration (total and p-tau) in a group of older schizophrenia patients and related them to cognitive and MRI measures. Older schizophrenia (n = 11), AD patients (n = 20) and elderly controls (n = 6) underwent cognitive testing, lumbar puncture, and MRI scanning. Abeta42 and total and p-tau concentrations were assayed in the CSF. MRI volumes were assessed using both voxel-based (cortical pattern matching) and region-of-interest analyses. RESULTS: CSF tau concentration in older schizophrenia patients was within normal limits (total tau 171 ± 51 pg/ml, p-tau 32 ± 8 pg/ml), while CSF Abeta42 (465 ± 112 pg/ml) levels were significantly lower compared to healthy elders (638 ± 130 pg/ml) but higher than in AD patients (352 ± 76 pg/ml). There was a strong positive relationship between CSF total or p-tau levels and MMSE scores in schizophrenia patients but not in AD, where higher concentrations of total tau were correlated with higher volumes in the occipital cortex (r = 0.63, p = 0.036), while in AD a significant correlation was found between lower Abeta42 concentrations and lower gray matter volume in the cingulate and lateral orbital cortices (r > 0.46, p < 0.05). CONCLUSIONS: Older schizophrenia patients show a peculiar pattern of CSF Abeta42 and tau concentrations that relates to cognitive and structural markers but is not consistent with neurodegeneration and could be secondary to neurodevelopmental or drug treatment effects.

Cortical changes in incipient Alzheimer's disease.

Mild cognitive impairment (MCI) is defined by memory impairment with no impact on daily activities. 10 to 15% of MCI convert to Alzheimer's disease (AD) per year. While structural changes in the cortex of AD patients have been extensively investigated, fewer studies analyzed changes in the years preceding conversion. 46 MCI patients and 20 healthy controls underwent structural 1.0T-weighted high-resolution MR scans at baseline and after 1.4 (SD 0.3) years. All subjects were assessed yearly for up to 4 years with a comprehensive neuropsychological battery. Sixteen of the 46 patients converted to AD (cMCI) while 30 remained stable (sMCI). An accurate voxel-based statistical mesh-model technique (cortical pattern matching) with a related region-of-interest analysis based on networks defined from a Brodmann area atlas (BAs) were used to map gray matter changes over time. At baseline, cMCI patients had 10 to 30% less cortical gray matter volume than healthy controls in regions known to be affected by AD pathology (entorhinal, temporoparietal, posterior cingulate, and orbitofrontal cortex, p=0.0001). Over time, cMCI patients lost more gray matter than sMCI in all brain areas but mainly in the olfactory and in the polysynaptic hippocampal network (more than 8% gray matter loss, p<0.024). sMCI patients had 10 to 20% less volume than controls in the posterior cingulate and orbitofrontal cortex (p<0.008) although their progression over time was significantly slower than cMCI. AD patients in the MCI stage show greater gray matter loss in the olfactory and polysynaptic hippocampal network. These findings are in line with neuropathological knowledge.

Markers of Alzheimer's disease in a population attending a memory clinic.

BACKGROUND: New marker-based criteria for the diagnosis of Alzheimer's disease (AD) were recently proposed. We describe their operational translation in 144 consecutive patients referred to our Memory Clinic. METHODS: Visual ratings of hippocampal atrophy and of cortical glucose hypometabolism in magnetic resonance imaging and positron emission tomography, and concentrations of total tau and Abeta1-42 in cerebrospinal fluid were assessed in 12 patients with subjective memory complaints (SMCs) (Mini-Mental State Examination [MMSE] score, 28.0 +/- 1.1 [mean +/- SD]), 37 with mild cognitive impairment (MCI) (MMSE, 25.1 +/- 3.6), 55 with AD (MMSE, 21.1 +/- 3.5), and 40 with non-AD dementia (MMSE, 21.6 +/- 5.5). RESULTS: The sensitivity for AD of each individual biomarker was higher (65% to 87%) than for MCI (18% to 50%). Each biomarker's specificity for SMC and non-AD dementias was good to moderate (83% and 53%). Positivity for at least one marker increased the probability 38 times of belonging to the AD group (P < 0.0001). CONCLUSION: The new diagnostic criteria can be operationalized in clinical routines, but longitudinal studies of MCI patients will need to assess the criteria's prognostic value.

In vivo neuropathology of cortical changes in elderly persons with schizophrenia.

BACKGROUND: Elderly schizophrenia patients frequently develop cognitive impairment of unclear etiology. Magnetic resonance imaging (MRI) studies revealed brain structural abnormalities, but the pattern of cortical gray matter (GM) volume and its relationship with cognitive and behavioral symptoms are unknown. METHODS: Magnetic resonance scans were taken from elderly schizophrenia patients (n = 20, age 67 +/- 6 SD, Mini-Mental State Examination [MMSE] 23 +/- 4), Alzheimer's disease (AD) patients (n = 20, age 73 +/- 9, MMSE 22 +/- 4), and healthy elders (n = 20, age 73 +/- 8, MMSE 29 +/- 1). Patients were assessed with a comprehensive neuropsychological and behavioral battery. Cortical pattern matching and a region-of-interest analysis, based on Brodmann areas (BAs), were used to map three-dimensional (3-D) profiles of differences in patterns of gray matter volume among groups. RESULTS: Schizophrenia patients had 10% and 11% lower total left and right GM volume than healthy elders (p < .001) and 7% and 5% more than AD patients (p = .06 and ns). Regions that had both significantly less gray matter than control subjects and gray matter volume as low as AD mapped to the cingulate gyrus and orbitofrontal cortex (BA 30, 23, 24, 32, 25, 11). The strongest correlate of gray matter volume in elderly schizophrenia patients, although nonsignificant, was the positive symptom subscale of the Positive and Negative Syndrome Scale, mapping to the right anterior cingulate area (r = .42, p = .06). CONCLUSIONS: The orbitofrontal/cingulate region had low gray matter volume in elderly schizophrenia patients. Neither cognitive impairment nor psychiatric symptoms were significantly associated with structural differences, even if positive symptoms tended to be associated with increased gray matter volume in this area.

In vivo mapping of incremental cortical atrophy from incipient to overt Alzheimer's disease.

Progressive brain atrophy is believed to be the Alzheimer's disease (AD) marker with the greatest evidence for validity. Mapping the topography of cortical atrophy throughout the stages of severity may allow the neural networks affected to be identified. Twenty healthy elderly persons (OH, MMSE 29.1 +/- 1.0), 11 patients with incipient AD (iAD, 26.5 +/- 2.0), 15 with mild AD (miAD, 23.5 +/- 2.2), and 15 with moderate AD (moAD, 16.5 +/- 2.0) underwent 3D magnetic resonance. Cortical pattern matching analysis was performed and maps of percent differences in gray matter distribution were computed between the following groups: iAD versus OH, miAD versus iAD, and moAD versus miAD. Compared to OH, iAD patients exhibited a mean cortical gray matter loss of 9-20% in areas encompassing the polysynaptic hippocampal pathway (posterior cingulate/retrosplenial and medial temporal cortex) and subgenual/orbitofrontal cortices, and a less widespread loss of 5-11% in other neocortical areas. Compared to iAD, miAD featured widespread mean gray matter loss of 14-19% in areas encompassing the direct hippocampal pathway (temporal pole, temporoparietal association cortex, and dorsal prefrontal cortex), sensorimotor, and visual cortex, with a less marked loss (7-9%) in the polysynaptic pathway areas. Compared to miAD, only atrophy in the primary sensorimotor cortex was still relatively marked in moAD, with a mean gray matter loss of 10-11%; the loss in other regions was generally below 10%. These findings suggest that the polysynaptic hippocampal pathway is affected in iAD, the direct pathway and sensorimotor and visual networks are affected in moAD, and the sensorimotor network is affected in moAD.

Resting EEG sources correlate with attentional span in mild cognitive impairment and Alzheimer's disease.

Previous evidence has shown that resting delta and alpha electroencephalographic (EEG) rhythms are abnormal in patients with Alzheimer's disease (AD) and its potential preclinical stage (mild cognitive impairment, MCI). Here, we tested the hypothesis that these EEG rhythms are correlated with memory and attention in the continuum across MCI and AD. Resting eyes-closed EEG data were recorded in 34 MCI and 53 AD subjects. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography (LORETA). These sources were correlated with neuropsychological measures such as Rey list immediate recall (word short-term memory), Rey list delayed recall (word medium-term memory), Digit span forward (immediate memory for digits probing focused attention), and Corsi span forward (visuo-spatial immediate memory probing focused attention). A statistically significant negative correlation (Bonferroni corrected, P < 0.05) was observed between Corsi span forward score and amplitude of occipital or temporal delta sources across MCI and AD subjects. Furthermore, a positive correlation was shown between Digit span forward score and occipital alpha 1 sources (Bonferroni corrected, P < 0.05). These results suggest that cortical sources of resting delta and alpha rhythms correlate with neuropsychological measures of immediate memory based on focused attention in the continuum of MCI and AD subjects.