Amyloid-positive Group Research Articles

EFFECT OF APOE-ε2 ON REGIONAL GRAY MATTER ATROPHY AND CLINICAL PHENOTYPE IN ALZHEIMER’S DISEASE

The APOE ε2 allele is considered a protective factor against developing Alzheimer's disease (AD). Consequently, the proportion of APOE ε2 carriers among AD patients is low (3–5%), but a small number of individuals do develop AD despite ε2 carriership. In this study, we characterized the neuropsychological profile and distribution of gray matter atrophy of ε2 carriers with MCI or dementia -due-to-AD. 38 ε2 carriers (all ε2/ε3) with a clinical diagnosis of MCI or dementia -due-to-AD based on positive amyloid PET and/or CSF amyloid-beta1–42 were included. This group was matched for age, sex and education with an amyloid-negative cognitively normal ε3/ε3 (NC) group, and groups of amyloid-positive ε3/ε3, ε3/ε4, and ε4/ε4 AD patients (Table 1). Neuropsychological test scores were converted into Z-scores using the mean and standard deviation of the NC group and then categorized into 4 cognitive domains (i.e. memory, attention, executive functioning and language). ANCOVA analyses adjusted for age, sex, education and disease-stage (MCI/ dementia) were used to compare cognition between AD groups. Voxel-based morphometry was conducted in statistical parametric mapping 12 to assess voxelwise differences in gray matter atrophy between AD groups and controls. The models included age, sex, scanner-type and total intracranial volume as covariates. ε2 carriers had more impaired language function compared to all other AD groups (F(3)=6.29, p<.01; Figure 1), while memory was relatively preserved in ε2 carriers compared to ε4/ε4 carriers (F(3)=2.67, p=.05). Voxelwise contrasts against controls revealed relative sparing of the medial temporal lobe in ε2 compared to ε4 carriers (p<.05, family-wise error corrected; Figure 2). Similar analyses using a less stringent threshold (p<.001, uncorrected; Figure 3) revealed that ε2 carriers displayed i) an atrophy pattern that was mostly restricted to temporoparietal regions compared to wider neocortical involvement in other groups, and ii) left>right asymmetry. The observed atrophy pattern in ε2 carriers (i.e. left>right asymmetry and relatively spared medial temporal lobes) matches their neuropsychological profile with prominent language deficits and relatively preserved memory performance. These results help to elucidate differences in regional vulnerability across APOE genotypes and better understand clinical heterogeneity in AD. Neuropsychological performance of all amyloid-positive groups across cognitive domains Z-scores, calculated based on the mean and standard deviation of the normal control group indicate better memory performance of ε2 compared to ε4/ε4 and worse language performance of ε2 compared to all groups. * significant contrast with ε2 carriers at α=.05, adjusted for age, sex, education and disease stage. Voxelwise contrasts between normal controls and amyloid-beta positive ε2, ε3/ε3, ε3/ε4 and ε4/ε4 AD patients, family-wise error corrected (p<0.05) Colored areas indicate regions where AD groups have significantly lower gray matter volume than normal controls. Voxelwise contrasts between normal controls and amyloid-beta positive ε2, ε3/ε3, ε3/ε4 and ε4/ε4 AD patients, (p<0.001, uncorrected for multiple comparisons) Colored areas indicate regions where AD groups have significantly lower gray matter volume than normal controls.

Detectable Neuropsychological Differences in Early Preclinical Alzheimer's Disease: A Meta-Analysis.

The development of methods for in vivo detection of cerebral beta amyloid retention and tau accumulation have been increasingly useful in characterizing preclinical Alzheimer's disease (AD). While the association between these biomarkers and eventual AD has been demonstrated among cognitively intact older adults, the link between biomarkers and neurocognitive ability remains unclear. We conducted a meta-analysis to test the hypothesis that cognitively intact older adults would show statistically discernable differences in neuropsychological performance by amyloid status (amyloid negative=A-, amyloid positive=A+). We secondarily hypothesized a third group characterized by either CSF tau pathology or neurodegeneration, in addition to amyloidosis (A+/N+ or Stage 2), would show lower neuropsychology scores than the amyloid positive group (A+/N- or Stage 1) when compared to the amyloid negative group. Pubmed, PsychINFO, and other sources were searched for relevant articles, yielding 775 total sources. After review for inclusion/exclusion criteria, duplicates, and risk of bias, 61 studies were utilized in the final meta-analysis. Results showed A+ was associated with poorer performance in the domains of global cognitive function, memory, language, visuospatial ability, processing speed, and attention/working memory/executive functions when compared to A-. A+/N+ showed lower performances on memory measures when compared to A+/N- in secondary analyses based on a smaller subset of studies. Results support the notion that neuropsychological measures are sensitive to different stages of preclinical AD among cognitively intact older adults. Further research is needed to determine what constitutes meaningful differences in neuropsychological performance among cognitively intact older adults.

Cognitive Event-Related Potential, an Early Diagnosis Biomarker in Frail Elderly Subjects: The ERP-MAPT-PLUS Ancillary Study.

By analyzing brain synaptic function, cognitive event-related potentials (ERPs) could provide powerful and innovative tools for early Alzheimer's disease (AD) diagnosis. We investigated the relevance of the ERP-P300 component as a potential diagnosis marker in elderly subjects at risk of developing AD. ERP-P300 was analyzed on 85 subjects recruited from the Multidomain Alzheimer Preventive Trial (MAPT). PET-AV45 brain imaging was available from 36 subjects. Two ERP-P300 subgroups were identified according to their PET-AV45 status: PET-Aβ positive (n = 15) and PET-Aβ negative (n = 21). In the amyloid positive group, we observed a highly significant increase in P3b latency in parietal brain regions (p = 0.0052). P3b in parietal regions correctly categorized 69.4% elderly subjects from the P300-PET Aβ positive group. Combined analysis of parietal P3b latencies and category fluency correctly classified 75% subjects from the P300-PET Aβ positive group. The P300 ERP presents good predictive measure of brain amyloid load and has the potential to be used as a screening instrument for preclinical AD. The incorporation of P3b latency may be used as an adjunctive tool with neuropsychological assessment (i.e., verbal category fluency) as a specific and sensitive method for preclinical assessment of AD.

Association of Higher Cortical Amyloid Burden With Loneliness in Cognitively Normal Older Adults

Emotional and behavioral symptoms in cognitively normal older people may be direct manifestations of Alzheimer disease (AD) pathophysiology at the preclinical stage, prior to the onset of mild cognitive impairment. Loneliness is a perceived state of social and emotional isolation that has been associated with cognitive and functional decline and an increased risk of incident AD dementia. We hypothesized that loneliness might occur in association with elevated cortical amyloid burden, an in vivo research biomarker of AD. To determine whether cortical amyloid burden is associated with greater loneliness in cognitively normal older adults. Cross-sectional analyses using data from the Harvard Aging Brain Study of 79 cognitively normal, community-dwelling participants. A continuous, aggregate measure of cortical amyloid burden, determined by Pittsburgh Compound B-positron emission tomography (PiB-PET), was examined in association with loneliness in linear regression models adjusting for age, sex, apolipoprotein E ε4 (APOEε4), socioeconomic status, depression, anxiety, and social network (without and with the interaction of amyloid and APOEε4). We also quantified the association of high amyloid burden (amyloid-positive group) to loneliness (lonely group) using logistic regression, controlling for the same covariates, with the amyloid-positive group and the lonely group, each composing 32% of the sample (n = 25). Loneliness, as determined by the 3-item UCLA Loneliness Scale (possible range, 3-12, with higher score indicating greater loneliness). The 79 participants included 43 women and 36 men with a mean (SD) age of 76.4 (6.2) years. Mean (SD) cortical amyloid burden via PiB-PET was 1.230 (0.209), and the mean (SD) UCLA-3 loneliness score was 5.3 (1.8). Twenty-two (28%) had positive APOEε4 carrier status, and 25 (32%) were in the amyloid-positive group with cortical PiB distribution volume ratio greater than 1.2. Controlling for age, sex, APOEε4, socioeconomic status, depression, anxiety, and social network, we found that higher amyloid burden was significantly associated with greater loneliness: compared with individuals in the amyloid-negative group, those in the amyloid-positive group were 7.5-fold (95% CI, 1.7-fold to 34.0-fold) more likely to be classified as lonely than nonlonely (β = 3.3, partial r = 0.4, P = .002). Furthermore, the association of high amyloid burden and loneliness was stronger in APOEε4 carriers than in noncarriers. We report a novel association of loneliness with cortical amyloid burden in cognitively normal older adults, suggesting that loneliness is a neuropsychiatric symptom relevant to preclinical AD. This work will inform new research into the neural underpinnings and disease mechanisms involved in loneliness and may enhance early detection and intervention research in AD.

Longitudinal Trajectories of Clinical Decline in Amyloid Positive and Negative Populations.

Brain beta-amyloid status portends different trajectories of clinical decline. Determine trajectories and predictive baseline variable(s). Longitudinal, up to 24 months. ADNI sites. Healthy control (n=325), early and late mild cognitive impairment (n=279; n=372), and Alzheimer's dementia (n=216) subjects from ADNI-1/GO/2. Baseline amyloid status was based on first available CSF Aβ1-42 or, [11C]PiB or [18F]florbetapir (FBP) PET. Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) and Functional Activities Questionnaire (FAQ) were co-analyzed using Growth Mixture Modeling (GMM) to define latent class trajectories for each amyloid group. Classification and Regression Tree (CART) analysis determined which variables best predicted trajectory class membership using a number of variables available to clinicians. GMMs found two trajectory classes (C1, C2) each for amyloid-positive (P; n=722) and negative (N; n=470) groups. Most (90%) in the negative group were C2N with mildly impaired baseline ADAS-Cog13, normal FAQ and nonprogression; 10% were C1N with moderately impaired baseline FAQ and ADAS-Cog13 and trajectory of moderately worsening scores on the FAQ. C1P (26%) had more impaired baseline FAQ and ADAS-Cog13 than C2P (74%) and a steeper declining trajectory. CART yielded 4 decision nodes (FAQ <10.5, FAQ <6.5, MMSE ≥26.5, age <75.5) in positive and 1 node (FAQ <6.5) in negative groups, with 91.4% and 92.8% accuracy for class assignments, respectively. The trajectory pattern of greater decline in amyloid positive subjects was predicted by greater baseline impairment of cognition and function. While most amyloid-negative subjects had nonprogression irrespective of their diagnosis, a subgroup declined similarly to the gradually declining amyloid-positive group. CART predicted likely trajectory class, with known amyloid status, using variables accessible in a clinical setting, but needs replication.

Amyloid and FDG-PET study of logopenic primary progressive aphasia: evidence for the existence of two subtypes.

The logopenic variant of primary progressive aphasia (lvPPA) has been associated with Alzheimer disease, although this relationship is still subject to debate. The purpose of this study is to determine the frequency of amyloid biomarkers in patients with lvPPA, and record any potential clinical or topographic differences between patients with and without amyloid deposits. We conducted cognitive examination and positron-emission tomography studies with fluorodeoxyglucose ((18)F) and florbetapir ((18)F) in a cohort of 16 patients diagnosed with lvPPA. We evaluated the prevalence of amyloid deposits as well as any clinical and metabolic differences between the groups with and without significant presence of amyloid deposits. Eleven patients (69 %) were considered amyloid-positive. The amyloid-positive group displayed less metabolic activity in the left temporoparietal region than the control group, while the amyloid-negative group showed lower metabolism in the left temporoparietal region extending to the anterior temporal and basal frontal regions. The percentage of change in patients with clinical and FDG-PET follow-up did not differ between the amyloid-positive and amyloid-negative subgroups. The frequency of amyloid-positive cases confirms that lvPPA is frequently associated with Alzheimer disease. Amyloid-negative patients show a different cerebral metabolic pattern. These findings show the relevance of using amyloid PET to study lvPPA, and also suggest that the logopenic variant may not be specific to Alzheimer disease in certain cases.

A-78 * Cognitively Normal Older Adults with Preclinical Alzheimer's Disease Demonstrate Slower Processing Speed on Everyday Financial Tasks

Objective: To investigate financial skills in preclinical Alzheimer's disease (AD) using a new short form measure of financial capacity. Method: In collaboration with the Mayo Clinic Study of Aging, we recruited 94 cognitively normal, community dwelling older adults age 70+ in Olmsted County, Minnesota. All participants completed 11C Pittsburgh compound B PET imaging (PiB), and a short-form version of the Financial Capacity Instrument (FCI-SF). The FCI-SF measures performance accuracy on a series of everyday financial tasks, and also measures time to completion (in seconds) of four specific tasks: a medical deductible calculation, a simple income tax calculation, completion of a single-item checkbook/register task, and completion of a three-item checkbook/register task. We compared amyloid positive and negative cognitively normal subjects on their FCI-SF total performance score, and on the four timing variables, using a Rank Sum test. Results: Amyloid imaging resulted in a subdivision of the sample into groups of amyloid positive (n = 26) and amyloid negative cognitively normal subjects (n = 68). FCI-SF total score performance did not differ across groups (p = 0.47). However, the amyloid positive group was slower completing the two checkbook tasks (composite time) (p = .045), and the four financial tasks as a whole (composite time) (p = .017). Conclusion(s): Older cognitively normal subjects with a biomarker for preclinical AD performed equivalently with amyloid negative older subjects in accurately conducting different everyday financial tasks, but showed significantly slower time completing the tasks. These findings suggest that diminished processing speed is an initial preclinical change signaling future financial declines in patients with AD.

Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity

To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity. Cognitively normal (CN) participants in the Mayo Clinic Study of Aging who had 2 or more serial imaging assessments, which included amyloid PET, FDG-PET, and MRI at each time point, were eligible for analysis (n = 207). Twelve subjects with Alzheimer disease dementia were included for comparison. Of the 123 CN participants who were amyloid-negative at baseline, 26 met criteria for incident amyloid PET positivity. Compared to the 69 subjects who remained stable amyloid-negative, on average these 26 did not differ on any imaging, demographic, or cognitive variables except amyloid PET (by definition) and task-free functional connectivity, which at baseline was greater in the incident amyloid-positive group. Eleven of the 26 incident amyloid-positive subjects had abnormal hippocampal volume, FDG-PET, or both at baseline. The incidence of amyloid PET positivity is approximately 13% per year among CN participants over age 70 sampled from a population-based cohort. In 15/26 (58%), incident amyloid positivity occurred prior to abnormalities in FDG-PET and hippocampal volume. However, 11/26 (42%) incident amyloid-positive subjects had evidence of neurodegeneration prior to incident amyloid positivity. These 11 could be subjects with combinations of preexisting non-Alzheimer pathophysiologies and tau-mediated neurodegeneration who newly entered the amyloid pathway. Our findings suggest that both "amyloid-first" and "neurodegeneration-first" biomarker profile pathways to preclinical AD exist.