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1.  Neuroimaging and Other Biomarkers for Alzheimer's Disease: The Changing Landscape of Early Detection 
The goal of this review is to provide an overview of biomarkers for Alzheimer's disease (AD), with emphasis on neuroimaging and cerebrospinal fluid (CSF) biomarkers. We first review biomarker changes in patients with late-onset AD, including findings from studies using structural and functional magnetic resonance imaging (MRI), advanced MRI techniques (diffusion tensor imaging, magnetic resonance spectroscopy, perfusion), positron emission tomography with fluorodeoxyglucose, amyloid tracers, and other neurochemical tracers, and CSF protein levels. Next, we evaluate findings from these biomarkers in preclinical and prodromal stages of AD including mild cognitive impairment (MCI) and pre-MCI conditions conferring elevated risk. We then discuss related findings in patients with dominantly inherited AD. We conclude with a discussion of the current theoretical framework for the role of biomarkers in AD and emergent directions for AD biomarker research.
PMCID: PMC3955298  PMID: 23297785
mild cognitive impairment (MCI); preclinical Alzheimer's disease (AD); magnetic resonance imaging (MRI); functional MRI (fMRI); positron emission tomography (PET); cerebrospinal fluid (CSF); genetics
2.  Neuropsychiatric symptoms in MCI subtypes: the importance of executive dysfunction 
Mild cognitive impairment (MCI) is a syndrome thought to be a prodrome of dementia for some patients. One subtype, amnestic MCI, may be specifically predispose patients to develop Alzheimer’s Dementia (AD). Since dementia has been associated with a range of neuropsychiatric symptoms (NPS), we sought to examine the prevalence of NPS in MCI and its subtypes.
1779 participants in the National Alzheimer Coordinating Center (NACC) with MCI were included in this study. All participants were evaluated systematically with a thorough cognitive battery, clinical interview, and consensus diagnoses, and subtyped as: 1) amnestic (aMCI) (single- or multiple-domain) vs. non-amnestic (non-aMCI); 2) executive dysfunction-MCI (exMCI) (single- or multiple-domain) vs. no executive dysfunction-MCI (non-exMCI); 3) both aMCI and exMCI; 4) and neither aMCI nor exMCI. Additionally , aMCI vs. nonaMCI and exMCI vs. non-exMCI dichotomies were explored. NPS were assessed with the Neuropsychiatric Inventory (NPI-Q) and Geriatric Depression Scale (GDS).
1379 participants (77.5%) met criteria for aMCI and 616 (34.6%) for exMCI. No differences were observed in the prevalence of NPS between aMCI vs. non-aMCI. However, exMCI was associated with greater severity of depression, anxiety, agitation, disinhibition, irritability, and sleep problems, although these differences do not persist after adjustment for several variables. .
While there were few associations between aMCI and NPS, the presence of executive dysfunction in MCI was associated with greater severity of symptoms and specifically with depression (evidenced by GDS score) and anxiety. These findings may have implications for MCI prognosis and need to be explored in longitudinal studies.
PMCID: PMC3204866  PMID: 20845402
Mild Cognitive Impairment; Depression; Executive Dysfunction; Neuropsychiatric symptoms
3.  Visual contrast sensitivity in AD, MCI, & older adults with cognitive complaints 
Neurobiology of aging  2012;34(4):1133-1144.
Deficits in contrast sensitivity (CS) have been reported in Alzheimer’s disease (AD). However, the extent of these deficits in prodromal AD stages, including mild cognitive impairment (MCI) or even earlier, has not been investigated. In this study, CS was assessed using frequency doubling technology (FDT) in older adults with AD (n=10), amnestic MCI (n=28), cognitive complaints without performance deficits (CC, n=20), and healthy controls (HC, n=29). The association between CS and cognition was also evaluated. Finally, the accuracy of CS measures for classifying MCI versus HC was evaluated.
CS deficits were found in AD and MCI, while CC showed intermediate performance between MCI and HC. Upper right visual field CS showed the most significant difference among groups. CS was also associated with cognitive performance. Finally, CS measures accurately classified MCI versus HC. The CS deficits in AD and MCI, and intermediate performance in CC, indicate that these measures are sensitive to early AD-associated changes. Therefore, FDT-based measures of CS may have promise as a novel AD biomarker.
PMCID: PMC3545045  PMID: 23084085
contrast sensitivity (CS); frequency doubling technology (FDT); Alzheimer’s disease (AD); mild cognitive impairment (MCI); cognitive complaints; biomarker; vision
4.  Intra-Individual Reaction Time Variability in Mild Cognitive Impairment and Alzheimer’s Disease: Gender, Processing Load and Speed Factors 
PLoS ONE  2013;8(6):e65712.
Compared to cognitively healthy ageing (CH), intra-individual variability in reaction time (IIVRT), a behavioural marker of neurological integrity, is commonly reported to increase in both Alzheimer’s disease (AD) and mild cognitive impairment (MCI). It varies in MCI with respect to whether it represents the pro-dromal stages of dementia or not; being greatest in those most likely to convert. Abnormal IIVRT in MCI therefore represents a potential measure of underlying functional integrity that may serve to differentiate MCI from CH and to help identify those patients for whom MCI is the result of a progressive pathological process. As the clinical approach to MCI is increasingly stratified with respect to gender, we investigated whether this factor could influence study outcome. The influence of RTSPEED and processing load upon IIVRT was also examined. Under low processing load conditions, IIVRT was significantly increased in both MCI and AD compared to CH. However, correcting for an individual’s processing speed abolished this effect in MCI but not in AD, indicating that the increased IIVRT in MCI and AD may result from different factors. In MCI but not in CH, IIVRT was significantly greater for females. Increasing task processing load by adding distracting information, although increasing overall IIVRT, failed to improve the differentiation between CH and both MCI and AD, and in MCI resulted in a reduction in the influence of gender upon study outcome. The outcome of studies investigating IIVRT in MCI and AD compared to CH therefore appear influenced by the gender of the participants, by task-related processing load and processing speed.
PMCID: PMC3677873  PMID: 23762413
5.  Relationship between baseline brain metabolism measured using [18F]FDG PET and memory and executive function in prodromal and early Alzheimer's disease 
Brain imaging and behavior  2012;6(4):568-583.
Differences in brain metabolism as measured by FDG-PET in prodromal and early Alzheimer's disease (AD) have been consistently observed, with a characteristic parietotemporal hypometabolic pattern. However, exploration of brain metabolic correlates of more nuanced measures of cognitive function has been rare, particularly in larger samples. We analyzed the relationship between resting brain metabolism and memory and executive functioning within diagnostic group on a voxel-wise basis in 86 people with AD, 185 people with mild cognitive impairment (MCI), and 86 healthy controls (HC) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We found positive associations within AD and MCI but not in HC. For MCI and AD, impaired executive functioning was associated with reduced parietotemporal metabolism, suggesting a pattern consistent with known AD-related hypometabolism. These associations suggest that decreased metabolic activity in the parietal and temporal lobes may underlie the executive function deficits in AD and MCI. For memory, hypometabolism in similar regions of the parietal and temporal lobes were significantly associated with reduced performance in the MCI group. However, for the AD group, memory performance was significantly associated with metabolism in frontal and orbitofrontal areas, suggesting the possibility of compensatory metabolic activity in these areas. Overall, the associations between brain metabolism and cognition in this study suggest the importance of parietal and temporal lobar regions in memory and executive function in the early stages of disease and an increased importance of frontal regions for memory with increasing impairment.
PMCID: PMC3532575  PMID: 23179062
mild cognitive impairment (MCI); Alzheimer's disease (AD); FDG PET; memory; executive function
6.  Anosognosia in mild cognitive impairment: Relationship to activation of cortical midline structures involved in self-appraisal 
Awareness of cognitive dysfunction shown by individuals with Mild Cognitive Impairment (MCI), a condition conferring risk for Alzheimer’s disease (AD), is variable. Anosognosia, or unawareness of loss of function, is beginning to be recognized as an important clinical symptom of MCI. However, little is known about the brain substrates underlying this symptom. We hypothesized that MCI participants’ activation of cortical midline structures (CMS) during self-appraisal would covary with level of insight into cognitive difficulties (indexed by a discrepancy score between patient and informant ratings of cognitive decline in each MCI participant). To address this hypothesis, we first compared 16 MCI participants and 16 age-matched controls, examining brain regions showing conjoint or differential BOLD response during self-appraisal. Second, we used regression to investigate the relationship between awareness of deficit in MCI and BOLD activity during self-appraisal, controlling for extent of memory impairment. Between-group comparisons indicated that MCI participants show subtly attenuated CMS activity during self-appraisal. Regression analysis revealed a highly-significant relationship between BOLD response during self-appraisal and self-awareness of deficit in MCI. This finding highlights the level of anosognosia in MCI as an important predictor of response to self-appraisal in cortical midline structures, brain regions vulnerable to changes in early AD.
PMCID: PMC2654607  PMID: 17445294
Magnetic Resonance Imaging; Self Assessment (Psychology); Agnosia; Alzheimer disease; Neocortex; Aging
7.  Everyday episodic memory in amnestic mild cognitive impairment: a preliminary investigation 
BMC Neuroscience  2011;12:80.
Decline in episodic memory is one of the hallmark features of Alzheimer's disease (AD) and is also a defining feature of amnestic Mild Cognitive Impairment (MCI), which is posited as a potential prodrome of AD. While deficits in episodic memory are well documented in MCI, the nature of this impairment remains relatively under-researched, particularly for those domains with direct relevance and meaning for the patient's daily life. In order to fully explore the impact of disruption to the episodic memory system on everyday memory in MCI, we examined participants' episodic memory capacity using a battery of experimental tasks with real-world relevance. We investigated episodic acquisition and delayed recall (story-memory), associative memory (face-name pairings), spatial memory (route learning and recall), and memory for everyday mundane events in 16 amnestic MCI and 18 control participants. Furthermore, we followed MCI participants longitudinally to gain preliminary evidence regarding the possible predictive efficacy of these real-world episodic memory tasks for subsequent conversion to AD.
The most discriminating tests at baseline were measures of acquisition, delayed recall, and associative memory, followed by everyday memory, and spatial memory tasks, with MCI patients scoring significantly lower than controls. At follow-up (mean time elapsed: 22.4 months), 6 MCI cases had progressed to clinically probable AD. Exploratory logistic regression analyses revealed that delayed associative memory performance at baseline was a potential predictor of subsequent conversion to AD.
As a preliminary study, our findings suggest that simple associative memory paradigms with real-world relevance represent an important line of enquiry in future longitudinal studies charting MCI progression over time.
PMCID: PMC3160963  PMID: 21816065
8.  Electrophysiological Correlates of Amnestic Mild Cognitive Impairment in a Simon Task 
PLoS ONE  2013;8(12):e81506.
Amnestic mild cognitive impairment (aMCI) represents a prodromal stage of Alzheimer`s disease (AD), especially when additional cognitive domains are affected (Petersen et al., 2009). Thus, single-domain amnestic MCI (sdaMCI) and multiple-domain-amnestic MCI (mdaMCI) biomarkers are important for enabling early interventions to help slow down progression of the disease. Recording event-related potentials (ERPs) is a non-invasive and inexpensive measure of brain activity associated with cognitive processes, and it is of interest from a clinical point of view. The ERP technique may also be useful for obtaining early sdaMCI and mdaMCI biomarkers because ERPs are sensitive to impairment in processes that are not manifested at behavioral or clinical levels. In the present study, EEG activity was recorded in 25 healthy participants and 30 amnestic MCI patients (17 sdaMCI and 13 mdaMCI) while they performed a Simon task. The ERPs associated with visuospatial (N2 posterior-contralateral – N2pc -) and motor (lateralized readiness potential – LRP –) processes were examined. The N2pc amplitude was smaller in participants with mdaMCI than in healthy participants, which indicated a decline in the correlates of allocation of attentional resources to the target stimulus. In addition, N2pc amplitude proved to be a moderately good biomarker of mdaMCI subtype (0.77 sensitivity, 0.76 specificity). However, the LRP amplitude was smaller in the two MCI groups (sdaMCI and mdaMCI) than in healthy participants, revealing a reduction in the motor resources available to execute the response in sdaMCI and mdaMCI patients. Furthermore, the LRP amplitude proved to be a valid biomarker (0.80 sensitivity, 0.92 specificity) of both amnestic MCI subtypes.
PMCID: PMC3855269  PMID: 24339941
9.  Proton MRS in Mild Cognitive Impairment 
Mild cognitive impairment (MCI) is a clinical syndrome operationalized for early diagnosis and treatment of Alzheimer’s disease (AD). Many individuals with MCI are at the prodromal stage of AD or other dementia. Various quantitative MR techniques that measure the anatomic, biochemical, microstructural, functional, and blood-flow changes are being evaluated as possible surrogate measures for early diagnosis and disease progression in AD. The pathology underlying MCI heterogenous, dominated by AD, cerebrovascular disease, Lewy body disease, or a mixture of these pathologies in community-based autopsy cohorts. Proton MRS metabolite markers may help identify and track etiologies that typically underlie MCI in the elderly. The role of proton MRS will especially be critical for pathophysiological processes for which a reliable biomarker does not exist such as glial and microglial activation in neurodegenerative dementia.
PMCID: PMC3609038  PMID: 23526756
Mild cognitive impairment; magnetic resonance spectroscopy; dementia; Alzheimer’s disease
10.  Mild cognitive impairment (MCI) in medical practice: a critical review of the concept and new diagnostic procedure. Report of the MCI Working Group of the European Consortium on Alzheimer's Disease 
Mild cognitive impairment (MCI) was proposed as a nosological entity referring to elderly people with mild cognitive deficit but no dementia. MCI is a heterogeneous clinical entity with multiple sources of heterogeneity. The concept of MCI was reviewed and a diagnostic procedure with three different stages was proposed by the European Consortium on Alzheimer's Disease Working Group on MCI. Firstly, MCI should correspond to cognitive complaints coming from the patients or their families; the reporting of a relative decline in cognitive functioning during the past year by a patient or informant; cognitive disorders as evidenced by clinical evaluation; absence of major repercussions on daily life; and absence of dementia. These criteria, similar to those defined during an international workshop in Stockholm, make it possible to identify an MCI syndrome, which is the first stage of the diagnostic procedure. Secondly, subtypes of MCI had to be recognised. Finally, the aetiopathogenic subtype could be identified. Identifying patients at a high risk for progression to dementia and establishing more specific and adapted therapeutic strategies at an early stage, together with more structured overall management, is made possible by the diagnostic procedure proposed.
PMCID: PMC2077456  PMID: 16549412
11.  Amyloid imaging in prodromal Alzheimer's disease 
Patients with mild cognitive impairment are at an increased risk of progression to Alzheimer's disease. However, not all patients with mild cognitive impairment progress, and it is difficult to accurately identify those patients who are in the prodromal stage of Alzheimer's disease. In a recent paper, Koivunen and colleagues report that Pittsburgh compound-B, an amyloid-beta positron emission tomography ligand, predicts the progression of patients with mild cognitive impairment to Alzheimer's disease. Of 29 subjects with mild cognitive impairment, 21 (72%) had a positive Pittsburgh compound-B positron emission tomography baseline scan. In their study, 15 of these 21 (71%) patients progressed to Alzheimer's disease, whilst only 1 out of 8 (12.5%) Pittsburgh compound-B-negative patients with mild cognitive impairment did so. Moreover, in these mild cognitive impairment patients, the overall amyloid burden increased approximately 2.5% during the follow-up period. This is consistent with other longitudinal amyloid imaging studies that found a similar increase in amyloid deposition over time in patients with mild cognitive impairment. These studies together challenge current theories that propose a flattening of the increase of brain amyloid deposition already in the preclinical stage of Alzheimer's disease. These findings may have important implications for the design of future clinical trials aimed at preventing progression to Alzheimer's disease by lowering the brain amyloid-beta burden in patients with mild cognitive impairment.
PMCID: PMC3218803  PMID: 21936965
12.  Bayesian Network Analysis Reveals Alterations to Default Mode Network Connectivity in Individuals at Risk for Alzheimer's Disease 
PLoS ONE  2013;8(12):e82104.
Alzheimer's disease (AD) is associated with abnormal functioning of the default mode network (DMN). Functional connectivity (FC) changes to the DMN have been found in patients with amnestic mild cognitive impairment (aMCI), which is the prodromal stage of AD. However, whether or not aMCI also alters the effective connectivity (EC) of the DMN remains unknown. We employed a combined group independent component analysis (ICA) and Bayesian network (BN) learning approach to resting-state functional MRI (fMRI) data from 17 aMCI patients and 17 controls, in order to establish the EC pattern of DMN, and to evaluate changes occurring in aMCI. BN analysis demonstrated heterogeneous regional convergence degree across DMN regions, which were organized into two closely interacting subsystems. Compared to controls, the aMCI group showed altered directed connectivity weights between DMN regions in the fronto-parietal, temporo-frontal, and temporo-parietal pathways. The aMCI group also exhibited altered regional convergence degree in the right inferior parietal lobule. Moreover, we found EC changes in DMN regions in aMCI were correlated with regional FC levels, and the connectivity metrics were associated with patients' cognitive performance. This study provides novel sights into our understanding of the functional architecture of the DMN and adds to a growing body of work demonstrating the importance of the DMN as a mechanism of aMCI.
PMCID: PMC3855765  PMID: 24324753
13.  Detection of Prodromal Alzheimer's Disease via Pattern Classification of MRI 
Neurobiology of aging  2006;29(4):514-523.
We report evidence that computer-based high-dimensional pattern classification of MRI detects patterns of brain structure characterizing mild cognitive impairment (MCI), often a prodromal phase of Alzheimer's Disease (AD). 90% diagnostic accuracy was achieved, using cross-validation, for 30 participants in the Baltimore Longitudinal Study of Aging. Retrospective evaluation of serial scans obtained during prior years revealed gradual increases in structural abnormality for the MCI group, often before clinical symptoms, but slower increase for individuals remaining cognitively normal. Detecting complex patterns of brain abnormality in very early stages of cognitive impairment has pivotal importance for the detection and management of AD.
PMCID: PMC2323584  PMID: 17174012
Prodromal Alzheimer's Disease; MCI; Pattern Recognition; MRI
14.  Neuropsychological Contributions to the Early Identification of Alzheimer’s Disease 
Neuropsychology review  2008;18(1):73-90.
A wealth of evidence demonstrates that a prodromal period of Alzheimer’s disease (AD) exists for some years prior to the appearance of significant cognitive and functional declines required for the clinical diagnosis. This prodromal period of decline is characterized by a number of different neuropsychological and brain changes, and reliable identification of individuals prior to the development of significant clinical symptoms remains a top priority of research. In this review we provide an overview of those neuropsychological changes. In particular, we examine specific domains of cognition that appear to be negatively affected during the prodromal period of AD, and we review newer analytic strategies designed to examine cognitive asymmetries or discrepancies between higher-order cognitive functions versus fundamental skills. Finally, we provide a critical examination of the clinical concept of Mild Cognitive Impairment and offer suggestions for an increased focus on the impact of cerebrovascular disease (CVD) and CVD risk during the prodromal period of AD.
PMCID: PMC2882236  PMID: 18347989
Neuropsychological contributions; Alzheimer’s disease; Prodromal expression; Mild Cognitive Impairment; Apolipoprotein E; Cerebrovascular; Very-Old
15.  Longitudinal progression of Alzheimer's-like patterns of atrophy in normal older adults: the SPARE-AD index 
Brain  2009;132(8):2026-2035.
A challenge in developing informative neuroimaging biomarkers for early diagnosis of Alzheimer's disease is the need to identify biomarkers that are evident before the onset of clinical symptoms, and which have sufficient sensitivity and specificity on an individual patient basis. Recent literature suggests that spatial patterns of brain atrophy discriminate amongst Alzheimer's disease, mild cognitive impairment (MCI) and cognitively normal (CN) older adults with high accuracy on an individual basis, thereby offering promise that subtle brain changes can be detected during prodromal Alzheimer's disease stages. Here, we investigate whether these spatial patterns of brain atrophy can be detected in CN and MCI individuals and whether they are associated with cognitive decline. Images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used to construct a pattern classifier that recognizes spatial patterns of brain atrophy which best distinguish Alzheimer's disease patients from CN on an individual person basis. This classifier was subsequently applied to longitudinal magnetic resonance imaging scans of CN and MCI participants in the Baltimore Longitudinal Study of Aging (BLSA) neuroimaging study. The degree to which Alzheimer's disease-like patterns were present in CN and MCI subjects was evaluated longitudinally in relation to cognitive performance. The oldest BLSA CN individuals showed progressively increasing Alzheimer's disease-like patterns of atrophy, and individuals with these patterns had reduced cognitive performance. MCI was associated with steeper longitudinal increases of Alzheimer's disease-like patterns of atrophy, which separated them from CN (receiver operating characteristic area under the curve equal to 0.89). Our results suggest that imaging-based spatial patterns of brain atrophy of Alzheimer's disease, evaluated with sophisticated pattern analysis and recognition methods, may be useful in discriminating among CN individuals who are likely to be stable versus those who will show cognitive decline. Future prospective studies will elucidate the temporal dynamics of spatial atrophy patterns and the emergence of clinical symptoms.
PMCID: PMC2714059  PMID: 19416949
early Alzheimer's disease; mild cognitive impairment; neuroimaging; ageing; SPARE-AD
16.  α-Synuclein in cerebrospinal fluid of Alzheimer’s disease and mild cognitive impairment 
In addition to amyloid beta (Aβ) and tau, α-synuclein, best known for its role in Parkinson’s disease (PD), has been suggested to be involved in cognition and pathogenesis of Alzheimer’s disease (AD). We investigate the potential of α-synuclein in cerebrospinal fluid (CSF) as a biomarker of cognitive decline in AD, and its prodromal phase, mild cognitive impairment (MCI). Using an established, sensitive Luminex assay, we measured α-synuclein levels in the CSF of a cohort of close to 400 healthy control, MCI and AD subjects obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and factored in APOE genotype in data analysis. CSF α-synuclein levels were significantly higher in the MCI (P = 0.005) and AD (P < 0.001) groups, compared to controls. However, receiver operating characteristic (ROC) curve analysis suggests that CSF α-synuclein level on its own only offered modest sensitivity (65 %) and specificity (74 %) as a diagnostic marker of AD, with an area under the curve (AUC) value of 0.719 for AD vs controls. The effect of APOE genotype, if any, was quite subtle. However, there was a significant correlation between α-synuclein and cognition (P = 0.001), with increased α-synuclein levels associated with decreased MMSE scores. Our results support a role for α-synuclein even in MCI, the early phase of AD, in addition to being a potential contributor in MCI and AD diagnosis or monitoring of disease progression.
PMCID: PMC3740054  PMID: 23603399
alpha-synuclein; Alzheimer’s disease; Mild cognitive impairment; biomarkers; cerebrospinal fluid
17.  Structural and functional biomarkers of prodromal Alzheimer's disease: a high-dimensional pattern classification study 
NeuroImage  2008;41(2):277-285.
This work builds upon previous studies that reported high sensitivity and specificity in classifying individuals with mild cognitive impairment (MCI), which is often a prodromal phase of Alzheimer's Disease (AD), via pattern classification of MRI scans. The current study integrates MRI and PET 15O water scans from 30 participants in the Baltimore Longitudinal Study of Aging, and tests the hypothesis that joint evaluation of structure and function can yield higher classification accuracy than either alone. Classification rates of up to 100% accuracy were achieved via leave-one-out cross validation, whereas conservative estimates of generalization performance in new scans, evaluated via bagging cross-validation, yielded an area under the receiver operating characteristic (ROC) curve equal to 0.978 (97.8%), indicating excellent diagnostic accuracy. Spatial maps of regions determined to contribute the most to the classification implicated many temporal, prefrontal, orbitofrontal, and parietal regions. Detecting complex patterns of brain abnormality in early stages of cognitive impairment has pivotal importance for the detection and management of AD.
PMCID: PMC2682533  PMID: 18400519
Alzheimer's Disease; MCI; high-dimensional Pattern Classification; MRI; PET; voxel-based analysis; diagnosis of AD
18.  Specific EEG Changes Associated with Atrophy of Hippocampus in Subjects with Mild Cognitive Impairment and Alzheimer's Disease 
We evaluated the association between hippocampal atrophy and increase of the EEG markers alpha3/alpha2 relative power ratio in mild cognitive impairment (MCI) and Alzheimer's disease patients. Seventy-nine subjects with MCI and 11 patients with AD underwent EEG recording and MRI scan. The MCI group was subdivided in three subgroups according to growing hippocampal atrophy. The groups were characterized by alpha3/alpha2 relative power ratio. In AD patients group mapped hippocampal regions were computed and related with alpha3/alpha2 power ratio. Results show that the increase of alpha3/alpha2 power ratio is correlated with atrophy of hippocampus both in MCI and in Alzheimer's disease patients. This finding confirms the possible diagnostic role of EEG markers as diagnostic and prognostic factors in patient with prodromal and declared Alzheimer's disease.
PMCID: PMC3296269  PMID: 22506130
19.  Requiring an amyloid-β1-42 biomarker for prodromal Alzheimer’s disease or mild cognitive impairment does not lead to more efficient clinical trials 
Low cerebrospinal fluid (CSF) amyloid-β1-42 concentration and high total-tau/Aβ1-42 ratio have been recommended to support the diagnosis of prodromal Alzheimer’s disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and also to select patients for clinical trials.
We tested this recommendation with clinical trials simulations using patients from the Alzheimer Disease Neuroimaging Initiative who fulfilled the following entry criteria: (1) aMCI, (2) aMCI with CSF Aβ1-42 ≤192 mg/mL, (3) and aMCI with total-tau/Aβ1-42 >.0.39. For each criterion, we randomly resampled the database obtaining samples for 1000 trials for each trial scenario, planning for 1 or 2 year trials with samples from 50 to 400 patients per treatment or placebo group, with up to 40% dropouts, outcomes after using the AD assessment scale-cognitive subscale and clinical dementia rating scale with effect sizes ranging from 0.15 to 0.75, and calculated statistical power.
Approximately 70% to 74% of aMCI patients with CSF measures met biomarker criteria. The addition of the low Aβ1-42 or high tau/Aβ1-42 requirement resulted in minimal or no increase in the power of the trials compared with enrolling aMCI without requiring the biomarker criteria. Slightly larger mean differences between the placebo and treatment groups fulfilling biomarker criteria were offset by increased outcome variability within the groups.
Although patients with aMCI or patients with prodromal AD meeting CSF biomarkers criteria were slightly more cognitively impaired and showed greater decline than patients with aMCI diagnosed without considering the biomarkers, the requirement of biomarker-positive patients would most likely not result in more efficient clinical trials, and trials would take longer because fewer patients would be available. A CSF Aβ1-42 marker, however, could be useful as an explanatory variable or covariate when warranted by the action of a drug.
PMCID: PMC2947209  PMID: 20813339
Alzheimer disease; Mild cognitive impairment; Biomarkers; Clinical trials; Simulations; Amyloid-beta protein; Alzheimer’s disease neuroimaging initiative (ADNI); Alzheimer’s disease assessment scale; Clinical dementia rating
20.  Detecting Subtle Changes in Visuospatial Executive Function and Learning in the Amnestic Variant of Mild Cognitive Impairment 
PLoS ONE  2011;6(7):e21688.
Background and Purpose
Amnestic mild cognitive impairment (aMCI) is a putative prodromal stage of Alzheimer's disease (AD) characterized by deficits in episodic verbal memory. Our goal in the present study was to determine whether executive dysfunction may also be detectable in individuals diagnosed with aMCI.
This study used a hidden maze learning test to characterize component processes of visuospatial executive function and learning in a sample of 62 individuals with aMCI compared with 94 healthy controls.
Relative to controls, individuals with aMCI made more exploratory/learning errors (Cohen's d = .41). Comparison of learning curves revealed that the slope between the first two of five learning trials was four times as steep for controls than for individuals with aMCI (Cohen's d = .64). Individuals with aMCI also made a significantly greater number of rule-break/error monitoring errors across learning trials (Cohen's d = .21).
These results suggest that performance on a task of complex visuospatial executive function is compromised in individuals with aMCI, and likely explained by reductions in initial strategy formulation during early visual learning and “on-line” maintenance of task rules.
PMCID: PMC3136468  PMID: 21779333
21.  Whole-brain Functional Networks in Cognitively Normal, Mild Cognitive Impairment, and Alzheimer’s Disease 
PLoS ONE  2013;8(1):e53922.
The conceptual significance of understanding functional brain alterations and cognitive deficits associated with Alzheimer’s disease (AD) process has been widely established. However, the whole-brain functional networks of AD and its prodromal stage, mild cognitive impairment (MCI), are not well clarified yet. In this study, we compared the characteristics of the whole-brain functional networks among cognitively normal (CN), MCI, and AD individuals by applying graph theoretical analyses to [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) data. Ninety-four CN elderly, 183 with MCI, and 216 with AD underwent clinical evaluation and FDG-PET scan. The overall small-world property as seen in the CN whole-brain network was preserved in MCI and AD. In contrast, individual parameters of the network were altered with the following patterns of changes: local clustering of networks was lower in both MCI and AD compared to CN, while path length was not different among the three groups. Then, MCI had a lower level of local clustering than AD. Subgroup analyses for AD also revealed that very mild AD had lower local clustering and shorter path length compared to mild AD. Regarding the local properties of the whole-brain networks, MCI and AD had significantly decreased normalized betweenness centrality in several hubs regionally associated with the default mode network compared to CN. Our results suggest that the functional integration in whole-brain network progressively declines due to the AD process. On the other hand, functional relatedness between neighboring brain regions may not gradually decrease, but be the most severely altered in MCI stage and gradually re-increase in clinical AD stages.
PMCID: PMC3545923  PMID: 23335980
22.  CERAD Neuropsychological Total Scores Reflect Cortical Thinning in Prodromal Alzheimer's Disease 
Sensitive cognitive global scores are beneficial in screening and monitoring for prodromal Alzheimer's disease (AD). Early cortical changes provide a novel opportunity for validating established cognitive total scores against the biological disease markers.
We examined how two different total scores of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery and the Mini-Mental State Examination (MMSE) are associated with cortical thickness (CTH) in mild cognitive impairment (MCI) and prodromal AD. Cognitive and magnetic resonance imaging (MRI) data of 22 progressive MCI, 78 stable MCI, and 98 control subjects, and MRI data of 103 AD patients of the prospective multicenter study were analyzed.
CERAD total scores correlated with mean CTH more strongly (r = 0.34-0.38, p < 0.001) than did MMSE (r = 0.19, p = 0.01). Of those vertex clusters that showed thinning in progressive MCI, 60-75% related to the CERAD total scores and 3% to the MMSE.
CERAD total scores are sensitive to the CTH signature of prodromal AD, which supports their biological validity in detecting early disease-related cognitive changes.
PMCID: PMC3919432  PMID: 24516412
Alzheimer's disease; Cognition; Cortical thickness; Magnetic resonance imaging; 
Memory; Neuropsychology; Mild cognitive impairment; AddNeuroMed study

23.  Functional impairment in elderly patients with mild cognitive impairment and mild Alzheimer's disease 
Archives of general psychiatry  2011;68(6):617-626.
The original mild cognitive impairment (MCI) criteria exclude substantial functional deficits, but recent reports suggest otherwise. Identifying the extent, severity, type, and correlates of functional deficits that occur in MCI and mild Alzheimer’s disease (AD) can aid in early detection of incipient dementia and identify potential mechanistic pathways to disrupted instrumental activities of daily living (IADLs).
To examine the number, type, and severity of functional impairments and identify the clinical characteristics associated with functional impairment across individuals with amnestic MCI (aMCI) and those with mild AD.
The study uses baseline data from the Alzheimer’s Disease Neuroimaging Initiative.
Data from the Alzheimer’s Disease Neuroimaging Initiative was collected at multiple research sites in the US and Canada.
The samples included 229 controls, 394 aMCI, and 193 AD patients.
The 10-item Pfeffer Functional Activities Questionnaire (FAQ) assessed function.
Informant-reported FAQ deficits were common in patients with aMCI (72.3%) and AD (97.4%) but were rarely self-reported by controls (7.9%). The average severity per FAQ deficit did not differ between patients with aMCI and controls; both were less impaired than patients with AD (P < .001). Two FAQ items (remembering appointments, family occasions, holidays, and medications; assembling tax records, business affairs, or other papers) were specific (0.95) in differentiating controls from the combined aMCI and AD groups (only 34.0% of patients with aMCI and 3.6% of patients with AD had no difficulty with these 2 items). The severity of FAQ deficits in the combined aMCI and AD group was associated with worse Trailmaking Test A scores and smaller hippocampal volumes (P < .001). Within the aMCI group, functionally intact individuals had greater hippocampal volumes and better Auditory Verbal Learning Test 30-minute delay and Trailmaking Test A (P < .001) scores compared with those with moderate or severe FAQ deficits. Patients with a high number of deficits were more likely to express the APOE ε4 allele (63.8%) compared with patients with no (46.8%) or few (48.4%) functional deficits.
Mild IADL deficits are common in individuals with aMCI and should be considered in MCI criteria. Two IADLs, remembering appointments, family occasions, holidays, and medications and assembling tax records, business affairs, or other papers, appear to be characteristic of clinically significant cognitive impairment. In patients with aMCI, impairment in memory and processing speed and greater medial temporal atrophy were associated with greater IADL deficits
PMCID: PMC3682408  PMID: 21646578
24.  Hippocampal Volumes, Proton Magnetic Resonance Spectroscopy Metabolites, and Cerebrovascular Disease in Mild Cognitive Impairment Subtypes 
Archives of neurology  2008;65(12):1621-1628.
Although a majority of patients with amnestic mild cognitive impairment (aMCI) progress to Alzheimer disease, the natural history of nonamnestic MCI (naMCI) is less clear. Noninvasive imaging surrogates for underlying pathological findings in MCI would be clinically useful for identifying patients who may benefit from disease-specific treatments at the prodromal stage of dementia.
To determine the characteristic magnetic resonance imaging (MRI) and proton MR spectroscopy (1H MRS) profiles of MCI subtypes.
Case-control study.
Community-based sample at a tertiary referral center.
Ninety-one patients with single-domain aMCI, 32 patients with multiple-domain aMCI, 20 patients with single- or multiple-domain naMCI, and 100 cognitively normal elderly subjects frequency-matched by age and sex.
Main Outcome Measures
Posterior cingulate gyrus 1H MRS metabolite ratios, hippocampal volumes, and cerebrovascular disease on MRI.
Patients with single-domain aMCI were characterized by small hippocampal volumes and elevated ratios of myo-inositol to creatine levels. Patients with naMCI on average had normal hippocampal volumes and 1H MRS metabolite ratios, but a greater proportion (3 of 20 patients [15%]) had cortical infarctions compared with patients with single-domain aMCI (6 of 91 [7%]). For characterization of MCI subtypes, 1H MRS and structural MRI findings were complementary.
The MRI and 1H MRS findings in singledomain aMCI are consistent with a pattern similar to that of Alzheimer disease. Absence of this pattern on average in patients with naMCI suggests that cerebrovascular disease and other neurodegenerative diseases may be contributing to the cognitive impairment in many individuals with naMCI.
PMCID: PMC2743393  PMID: 19064749
25.  Judgment in older adults: Development and psychometric evaluation of the Test of Practical Judgment (TOP-J) 
This article reports on the development and validation of a novel, objective test of judgment for use with older adults. The Test of Practical Judgment (TOP-J) is an open-ended measure that evaluates judgment related to safety, medical, social/ethical, and financial issues. Psychometric features were examined in a sample of 134 euthymic individuals with mild Alzheimer’s disease (AD), amnestic mild cognitive impairment (MCI), or cognitive complaints but intact neuropsychological performance (CC), and demographically-matched healthy controls (HC). Measures of reliability were adequate to high, and TOP-J scores correlated with select measures of executive functioning, language, and memory. AD participants obtained impaired TOP-J scores relative to HCs, while MCI and CC participants showed an intermediate level of performance. Confirmatory factor analyses were consistent with a unidimensional structure. Results encourage further development of the TOP-J as an indicator of practical judgment skills in clinical and research settings. Longitudinal assessments are being performed to examine predictive validity of the TOP-J for cognitive progression in our clinical groups.
PMCID: PMC3482485  PMID: 17896200

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