Natacha Lorius

Subjective cognitive complaints and amyloid burden in cognitively normal older individuals.

Accumulating evidence suggests that subjective cognitive complaints (SCC) may indicate subtle cognitive decline characteristic of individuals with preclinical Alzheimers disease (AD). In this study, we sought to build upon previous studies by associating SCC and amyloid-β deposition using positron emission tomography with Pittsburgh Compound B (PiB-PET) in cognitively normal older individuals. One-hundred thirty one subjects (mean age 73.5±6) were administered three subjective cognitive questionnaires and a brief neuropsychological battery. A relationship between a subjective memory complaints composite score and cortical PiB binding was found to be significant, even after controlling for depressive symptoms. By contrast, there were no significant relationships between objective cognitive measures of memory and executive functions and cortical PiB binding. Our study suggests that SCC may be an early indicator of AD pathology detectable prior to significant objective impairment.

Neuropsychiatric Symptoms and Global Functional Impairment along the Alzheimer’s Continuum

Background/Aims: Neuropsychiatric symptoms in Alzheimer’s disease (AD) are highly prevalent. We sought to determine whether neuropsychiatric symptoms were related to global functional impairment at baseline and over a 3-year period in older normal control (NC), mild cognitive impairment (MCI) and mild AD dementia subjects. Methods: Eight hundred and twelve subjects (229 NC, 395 MCI, 188 AD) from the Alzheimer’s Disease Neuroimaging Initiative study underwent cognitive and behavioral assessments over 3 years. Results: Greater hallucinations, anxiety and apathy were associated with greater global functional impairment at baseline, while the presence of hallucinations and apathy at baseline was associated with greater global functional impairment over time across all subjects. The following neuropsychiatric symptoms were not significantly associated with global functioning: delusions, agitation, depression, euphoria, disinhibition, irritability, aberrant motor behaviors, sleep and appetite. Conclusions: These results suggest that increased baseline hallucinations, apathy and anxiety are associated with current and future disease progression in AD.

Regional Cortical Thinning Predicts Worsening Apathy and Hallucinations Across the Alzheimer Disease Spectrum

OBJECTIVES To examine regions of cortical thinning and cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers associated with apathy and hallucinations in a continuum of individuals including clinically normal elderly, mild cognitive impairment, and mild AD dementia. DESIGN Cross-sectional and longitudinal studies. SETTING Fifty-seven research sites across North America. PARTICIPANTS Eight-hundred twelve community-dwelling volunteers; 413 participants in the CSF sub-study. MEASUREMENTS Structural magnetic resonance imaging data and CSF concentrations of amyloid-β 1-42, total tau, and phosphorylated tau derived from the Alzheimer Disease Neuroimaging Initiative database were analyzed. Apathy and hallucinations were measured at baseline and over 3 years using the Neuropsychiatric Inventory-Questionnaire. General linear models and mixed effects models were used to evaluate the relationships among baseline cortical thickness in seven regions, and baseline CSF biomarkers, apathy, and hallucinations at baseline and longitudinally. Covariates included diagnosis, sex, age, apolipoprotein E genotype, premorbid intelligence, memory performance, processing speed, antidepressant use, and AD duration. RESULTS Reduced baseline inferior temporal cortical thickness was predictive of increasing apathy over time, and reduced supramarginal cortical thickness was predictive of increasing hallucinations over time. There was no association with cortical thickness at baseline. CSF biomarkers were not related to severity of apathy or hallucinations in cross-sectional or longitudinal analyses. CONCLUSIONS These results suggest that greater baseline temporal and parietal atrophy is associated with worsening apathy and hallucinations in a large AD spectrum cohort, while adjusting for multiple disease-related variables. Localized cortical neurodegeneration may contribute to the pathophysiology of apathy and hallucinations and their adverse consequences in AD.

Validation of the Face Name Associative Memory Exam in Cognitively Normal Older Individuals

The recently developed Face Name Associative Memory Exam (FNAME), a challenging paired associative learning task, shows promise in detecting the subtle cognitive changes characteristic of preclinical Alzheimers disease. In this study, we evaluated the validity and reliability of the FNAME in 210 cognitively normal older individuals (58–90 years of age). Construct validity of the measure was assessed by principal components analysis, which revealed two independent factors. Correlations between the FNAME subtests and another episodic memory test were significant. The results indicated strong test–retest reliability in a subsample (n = 41). Normative data stratified by age were also generated.

Apathy Is Associated With Increased Amyloid Burden in Mild Cognitive Impairment

Apathy is the most common neuropsychiatric symptom in mild cognitive impairment (MCI) and Alzheimers disease (AD) dementia. The authors sought to determine whether apathy is associated with cortical amyloid burden, as measured by Pittsburgh Compound B (PiB) positron emission tomography (PET), and regional hypometabolism, measured by 18F-fluorodeoxyglocuse (FDG) PET in MCI. The authors found a significant association between increased apathy (lower Apathy Evaluation Scale score) and greater cortical PiB retention independent of age, but no significant association between apathy and regional FDG metabolism. These results suggest that increased apathy is associated with greater amyloid burden but not regional hypometabolism in MCI.

Vascular disease and risk factors are associated with cognitive decline in the alzheimer disease spectrum.

We investigated the relationship between vascular disease and risk factors versus cognitive decline cross-sectionally and longitudinally in normal older control, mild cognitive impairment, and mild Alzheimer disease (AD) dementia subjects. A total of 812 participants (229 normal older control, 395 mild cognitive impairment, 188 AD) underwent cognitive testing, brain magnetic resonance imaging, and clinical evaluations at baseline and over a period of 3 years. General linear, longitudinal mixed-effects, and Cox proportional hazards models were used. Greater homocysteine level and white matter hyperintensity volume were associated with processing speed impairment (homocysteine: P=0.02; white matter hyperintensity: P<0.0001); greater Vascular Index score was associated with memory impairment (P=0.007); and greater number of apolipoprotein E &egr;4 (APOE4) alleles was associated with global cognitive impairment (P=0.007) at baseline. Apolipoprotein E &egr;4 was associated with greater rate of increase in global cognitive impairment (P=0.002) and processing speed impairment (P=0.001) over time, whereas higher total cholesterol was associated with greater rate of increase in global cognitive impairment (P=0.02) and memory impairment (P=0.06) over time. These results suggest a significant association of increased vascular disease and risk factors with cognitive impairment at baseline and over time in the AD spectrum in a sample that was selected to have low vascular burden at baseline.

Apathy is Associated With Lower Inferior Temporal Cortical Thickness in Mild Cognitive Impairment and Normal Elderly Individuals

Apathy is a common neuropsychiatric symptom in Alzheimers disease dementia and amnestic mild cognitive impairment and is associated with cortical atrophy in Alzheimers disease dementia. This study investigated possible correlations between apathy and cortical atrophy in 47 individuals with mild cognitive impairment and 19 clinically normal elderly. Backward elimination multivariate linear regression was used to evaluate the cross-sectional relationship between scores on the Apathy Evaluation Scale and thickness of several cortical regions and covariates. Lower inferior temporal cortical thickness was predictive of greater apathy. Greater anterior cingulate cortical thickness was also predictive of greater apathy, suggesting an underlying reactive process.

Regional Cortical Thinning and Cerebrospinal Biomarkers Predict Worsening Daily Functioning Across the Alzheimer's Disease Spectrum

BACKGROUND Impairment in instrumental activities of daily living (IADL) heralds the transition from mild cognitive impairment (MCI) to dementia and is a major source of burden for both the patient and caregiver. OBJECTIVE To investigate the relationship between IADL and regional cortical thinning and cerebrospinal fluid (CSF) Alzheimers disease (AD) biomarkers cross-sectionally and longitudinally in clinically normal (CN) elderly, MCI, and mild AD dementia subjects. METHODS Two hundred and twenty nine CN, 395 MCI, and 188 AD dementia subjects participating in the Alzheimers Disease Neuroimaging Initiative underwent baseline magnetic resonance imaging, baseline lumbar puncture, and clinical assessments, including the Functional Activities Questionnaire used to measure IADL, every 6 to 12 months up to 3 years. General linear regression and mixed effects models were employed. RESULTS IADL impairment was associated with the interactions between lower inferior temporal cortical thickness and diagnosis (p < 0.0001), greater lateral occipital cortical thickness and diagnosis (p < 0.0001), and greater amyloid-β 1-42 (Aβ1-42) and diagnosis (p = 0.0002) at baseline (driven by AD dementia). Lower baseline supramarginal (p = 0.02) and inferior temporal (p = 0.05) cortical thickness, lower Aβ1-42 (p < 0.0001), and greater total tau (t-tau) (p = 0.02) were associated with greater rate of IADL impairment over time. CONCLUSIONS Temporal atrophy is associated with IADL impairment in mild AD dementia at baseline, while baseline parietal and temporal atrophy, lower CSF Aβ1-42, and greater t-tau predict worsening IADL impairment over time across the AD spectrum. These results emphasize the importance of assessing IADL at the stage of MCI and even at the transition from CN to MCI.

Regional fluorodeoxyglucose metabolism and instrumental activities of daily living across the Alzheimer's disease spectrum.

BACKGROUND Impairment in instrumental activities of daily living (IADL) begins as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimers disease (AD) dementia. IADL impairment in AD dementia has been associated with inferior parietal, inferior temporal, and superior occipital hypometabolism using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). OBJECTIVE To investigate the relationship between regional FDG metabolism and IADL in clinically normal (CN) elderly, MCI, and mild AD dementia subjects cross-sectionally and longitudinally. METHODS One hundred and four CN, 203 MCI, and 95 AD dementia subjects from the Alzheimers Disease Neuroimaging Initiative underwent clinical assessments every 6 to 12 months for up to three years and baseline FDG PET. The subjective, informant-based Functional Activities Questionnaire was used to assess IADL. General linear models and mixed effects models were used, covarying for demographics, cognition, and behavior. RESULTS The cross-sectional analysis revealed middle frontal and orbitofrontal hypometabolism were significantly associated with greater IADL impairment. Additionally, the interaction of diagnosis with posterior cingulate and with parahippocampal hypometabolism showed a greater decline in IADL performance as metabolism decreased for the AD dementia relative to the MCI group, and the MCI group relative to the CN group. The longitudinal analysis showed that baseline middle frontal and posterior cingulate hypometabolism were significantly associated with greater rate of increase in IADL impairment over time. CONCLUSION These results suggest that regional synaptic dysfunction, including the Alzheimer-typical medial parietal and less typical frontal regions, relates to daily functioning decline at baseline and over time across the early AD spectrum.

Regional cortical thinning predicts worsening apathy and hallucinations in mild cognitive impairment and mild Alzheimer's disease dementia

in white matter (WM) structural integrity. Diffusion tensor imaging (DTI) is a neuroimaging technique that allows in vivo assessment ofWMfiber tract integrity and, thus, could support the diagnosis of AD as an additional biomarker. Current research focuses on machine learning (ML) methods to automatically detect AD specific structural WM changes. Therefore, the algorithms used must be robust and stable to work with data recorded across different scanners.Within the newly created framework of the EuropeanDTI study in Dementia (EDSD) we have collected data of more than 330 subjects from ten scanners located at nine sites. Objective: To assess the accuracy of ML classifiers for the detection of AD based on a large multicenter DTI data set using different approaches to reduce inter-site variability.Methods: After strict quality control we pooled the remaining 280 DTI and MRI scans derived from 137 patients with clinically probable AD and 143 healthy elderly controls. For classification we used fractional anisotropy (FA) maps and mean diffusivity (MD) maps and performed a tenfold cross validation. We selected discriminative voxels using the information gain criterion and classified the data with a Support VectorMachine. In a second step, we eliminated variance attributable to center and other covariates including age, education, gender, using principal component analysis (PCA) before repeating the classification procedure. Results: For FA and MD the feature selection identified areas in themedial temporal lobe and corpus callosum that had the strongest contribution to the group separation. We achieved an accuracy of 80% for FA and 83% for MD. For the tissue density maps we obtained 83% for WM and 89% for gray matter. The reduction of variance components arising from center, gender, age and education effects did not significantly change the classification results for FA and MD. Conclusions:Multicenter acquisition of DTI data in combination with multivariate ML approaches show promising results which can be compared to earlier monocenter DTI studies. Variance introduced by different scanners can be detected by PCA, but it seems not to affect the performance of the classifier.