Liana G. Apostolova

The Cognitive Change Index as a Measure of Self and Informant Perception of Cognitive Decline: Relation to Neuropsychological Tests.

BACKGROUNDnThe perception of cognitive decline by individuals and those who know them well (informants) has been inconsistently associated with objective cognitive performance, but strongly associated with depressive symptoms.nnnOBJECTIVEnWe investigated associations of self-report, informant-report, and discrepancy between self- and informant-report of cognitive decline obtained from the Cognitive Change Index (CCI) with cognitive test performance and self-reported depressive symptoms.nnnMETHODSn267 participants with normal cognition, mild cognitive impairment (MCI), or mild dementia were included from a cohort study and memory clinic. Association of test performance and self-rated depression (Geriatric Depression Scale, GDS) with CCI scores obtained from subjects (CCI-S), their informants (CCI-I), and discrepancy scores between subjects and informants (CCI-D; CCI-S minus CCI-I) were analyzed using correlation and analysis of covariance (ANCOVA) models.nnnRESULTSnCCI-S and CCI-I scores showed high internal consistency (Cronbach alpha 0.96 and 0.98, respectively). Higher scores on CCI-S and CCI-I, and lower scores on the CCI-D, were associated with lower performance on various cognitive tests in both univariate and in ANCOVA models adjusted for age, gender, and education. Adjustment for GDS slightly weakened the relationships between CCI and test performance but most remained significant.nnnCONCLUSIONnSelf- and informant-report of cognitive decline, as measured by the CCI, show moderately strong relationships with objective test performance independent of age, gender, education, and depressive symptoms. The CCI appears to be a valid cross-sectional measure of self and informant perception of cognitive decline across the continuum of functioning. Studies are needed to address the relationship of CCI scores to longitudinal outcome.

Tau Imaging in Alzheimer’s Disease Diagnosis and Clinical Trials

In vivo imaging of the tau protein has the potential to aid in quantitative diagnosis of Alzheimer’s disease, corroborate or dispute the amyloid hypothesis, and demonstrate biomarker engagement in clinical drug trials. A host of tau positron emission tomography agents have been designed, validated, and tested in humans. Several agents have characteristics approaching the ideal imaging tracer with some limitations, primarily regarding off-target binding. Dozens of clinical trials evaluating imaging techniques and several pharmaceutical trials have begun to integrate tau imaging into their protocols.

Olfactory identification in subjective cognitive decline and mild cognitive impairment: Association with tau but not amyloid positron emission tomography

We investigated the association between olfactory identification and Alzheimers disease biomarkers, including amyloid, tau, and neurodegeneration.

Genome-wide association study of language performance in Alzheimer’s disease

HighlightsWe identified novel genetic variants associated with language performance.Minor allele variants in GLI3 are associated with worse language performance.Anatomical changes in language regions associated with language composite score.Developmental and glutamate pathways were related to lower language performance. Abstract Language impairment is common in prodromal stages of Alzheimer’s disease (AD) and progresses over time. However, the genetic architecture underlying language performance is poorly understood. To identify novel genetic variants associated with language performance, we analyzed brain MRI and performed a genome‐wide association study (GWAS) using a composite measure of language performance from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 1560). The language composite score was associated with brain atrophy on MRI in language and semantic areas. GWAS identified GLI3 (GLI family zinc finger 3) as significantly associated with language performance (p < 5 × 10−8). Enrichment of GWAS association was identified in pathways related to nervous system development and glutamate receptor function and trafficking. Our results, which warrant further investigation in independent and larger cohorts, implicate GLI3, a developmental transcription factor involved in patterning brain structures, as a putative gene associated with language dysfunction in AD.

Patient and Caregiver Assessment of the Benefits From the Clinical Use of Amyloid PET Imaging

Introduction: Few studies to date have explored patient and caregiver views on the clinical use of amyloid positron emission tomography (PET). Methods: A 7-item questionnaire assessing patient and caregiver views (510 total respondents) toward amyloid PET imaging was advertised broadly through alz.org/trialmatch. Results: We received 510 unique responses from 48 US states, 2 Canadian provinces, the Dominican Republic, and Greece. Both patients and caregivers indicated that they would want to receive amyloid imaging if offered the opportunity. Over 88% of respondents had a positive response (∼10% with neutral and 2% with negative responses) to whether amyloid PET should be offered routinely and be reimbursed. Such information was felt to be useful for long-term legal, financial, and health care planning. Respondents identifying with early age cognitive decline (younger than 65u2009y) were more likely to explore options for disability insurance (P=0.03). Responders from the Midwest were more likely to utilize information from amyloid imaging for legal planning (P=0.02), disability insurance (P=0.02), and life insurance (P=0.04) than other US regions. Discussion: Patients and caregivers supported the use of amyloid PET imaging in clinical practice and felt that the information would provide significant benefits particularly in terms of future planning.

Building a surface atlas of hippocampal subfields from high resolution T2-weighted MRI scans using landmark-free surface registration

The hippocampus is widely studied in neuroimaging field as it plays important roles in memory and learning. However, the critical subfield information is often not explored in most hippocampal studies. We previously proposed a method for hippocampal subfield morphometry by integrating FreeSurfer, FSL, and SPHARM tools. But this method had some limitations, including the analysis of T1-weighted MRI scans without detailed subfield information and hippocampal registration without using important subfield information. To bridge these gaps, in this work, we propose a new framework for building a surface atlas of hippocampal subfields from high resolution T2-weighted MRI scans by integrating state-of-the-art methods for automated segmentation of hippocampal subfields and landmark-free, subfield-aware registration of hippocampal surfaces. Our experimental results have shown the promise of the new framework.

EXAMINING THE EFFECT OF THE TOP 20 ALZHEIMER'S DISEASE RISK VARIANTS ON BRAIN AMYLOIDOSIS, STRUCTURAL ATROPHY AND METABOLISM

ALZHEIMER’S DISEASE RISK VARIANTS ON BRAIN AMYLOIDOSIS, STRUCTURAL ATROPHY AND METABOLISM Liana G. Apostolova, Shannon L. Risacher, Tugce Duran, Eddie Stage Jr., Naira Goukasian, John D. West, Triet Do, Jonathan Grotts, Kwangsik Nho, David Elashoff, Andrew J. Saykin, Indiana University School of Medicine, Indianapolis, IN, USA; Indiana University Medical School, Indianapolis, IN, USA; University of California, Los Angeles, Los Angeles, CA, USA. Contact e-mail: lapostol@ iu.edu

Towards Subject and Diagnostic Identifiability in the Alzheimer's Disease Spectrum Based on Functional Connectomes.

Alzheimer’s disease (AD) is the only major cause of mortality in the world without an effective disease modifying treatment. Evidence supporting the so called “disconnection hypothesis” suggests that functional connectivity biomarkers may have clinical potential for early detection of AD. However, known issues with low test-retest reliability and signal to noise in functional connectivity may prevent accuracy and subsequent predictive capacity. We validate the utility of a novel principal component based diagnostic identifiability framework to increase separation in functional connectivity across the Alzheimer’s spectrum by identifying and reconstructing FC using only AD sensitive components or connectivity modes. We show that this framework (1) increases test-retest correspondence and (2) allows for better separation, in functional connectivity, of diagnostic groups both at the whole brain and individual resting state network level. Finally, we evaluate a posteriori the association between connectivity mode weights with longitudinal neurocognitive outcomes.

Neuronal pentraxin 1: A synaptic-derived plasma biomarker in Alzheimer's disease

Synaptic neurodegeneration is thought to be an early event initiated by soluble β-amyloid (Aβ) aggregates that closely correlates with cognitive decline in Alzheimer disease (AD). Apolipoprotein ε4 (APOE4) is the most common genetic risk factor for both familial AD (FAD) and sporadic AD; it accelerates Aβ aggregation and selectively impairs glutamate receptor function and synaptic plasticity. However, its molecular mechanisms remain elusive and these synaptic deficits are difficult to monitor. AD- and APOE4-dependent plasma biomarkers have been proposed, but synapse-related plasma biomarkers are lacking. We evaluated neuronal pentraxin 1 (NP1), a potential CNS-derived plasma biomarker of excitatory synaptic pathology. NP1 is preferentially expressed in brain and involved in glutamate receptor internalization. NP1 is secreted presynaptically induced by Aβ oligomers, and implicated in excitatory synaptic and mitochondrial deficits. Levels of NP1 and its fragments were increased in a correlated fashion in both brain and plasma of 7-8u202fmonth-old E4FAD mice relative to E3FAD mice. NP1 was also found in exosome preparations and reduced by dietary DHA supplementation. Plasma NP1 was higher in E4FAD+ (APOE4+/+/FAD+/-) relative to E4FAD- (non-carrier; APOE4+/+/FAD-/-) mice, suggesting NP1 is modulated by Aβ expression. Finally, relative to normal elderly, plasma NP1 was also elevated in patients with mild cognitive impairment (MCI) and elevated further in the subset who progressed to early-stage AD. In those patients, there was a trend towards increased NP1 levels in APOE4 carriers relative to non-carriers. These findings indicate that NP1 may represent a potential synapse-derived plasma biomarker relevant to early alterations in excitatory synapses in MCI and early-stage AD.

Volumetric comparison of hippocampal subfields extracted from 4-minute accelerated vs. 8-minute high-resolution T2-weighted 3T MRI scans

The hippocampus has been widely studied using neuroimaging, as it plays an important role in memory and learning. However, hippocampal subfield information is difficult to capture by standard magnetic resonance imaging (MRI) techniques. To facilitate morphometric study of hippocampal subfields, ADNI introduced a high resolution (0.4xa0mm in plane) T2-weighted turbo spin-echo sequence that requires 8xa0min. With acceleration, the protocol can be acquired in 4xa0min. We performed a comparative study of hippocampal subfield volumes using standard and accelerated protocols on a Siemens Prisma 3T MRI in an independent sample of older adults that included 10 cognitively normal controls, 9 individuals with subjective cognitive decline, 10 with mild cognitive impairment, and 6 with a clinical diagnosis of Alzheimer’s disease (AD). The Automatic Segmentation of Hippocampal Subfields (ASHS) software was used to segment 9 primary labeled regions including hippocampal subfields and neighboring cortical regions. Intraclass correlation coefficients were computed for reliability tests between 4 and 8xa0min scans within and across the four groups. Pairwise group analyses were performed, covaried for age, sex and total intracranial volume, to determine whether the patterns of group differences were similar using 4 vs. 8xa0min scans. The 4 and 8xa0min protocols, analyzed by ASHS segmentation, yielded similar volumetric estimates for hippocampal subfields as well as comparable patterns of differences between study groups. The accelerated protocol can provide reliable imaging data for investigation of hippocampal subfields in AD-related MRI studies and the decreased scan time may result in less vulnerability to motion.