CRHD Connectomics in Brain Aging and Dementia

Study Overview

The Connectomics in Brain Aging and Dementia Project (CBA) will address specific questions related to structure, function, AD, aging and vascular disease in multi-modality studies leveraging the differential advantages of MRI, fMRI, MEG, and in vivo Aβ imaging. 

The CBA will enroll 200 individuals from the University of Pittsburgh Alzheimer's Disease Research Center: 125 with AD, and 75 with prodromal AD including 25 individuals with subjective memory complaints (but no objective impairments), and 50 patients with Mild Cognitive Impairment (MCI) from early through late-stage. The patient group will be age stratified (50 per decade) from ages 50-89, with equal representation of African-Americans and women.  The CBA will enroll 200 cognitively normal individuals, 50-89 years old, from ongoing studies of community-dwelling elders. The sample will be age stratified (50 per decade) with equal representation of African-Americans and women.  

In collaboration with the University of Pittsburgh ADRC Neuroimaging Core, the CBA will complete the HCP-specified structural imaging and cognitive evaluations on all 400 enrollees.

Study Timespan: June 1, 2016 - May 31, 2020



Investigators

James Becker

James Becker, Ph.D. - UPitt Principal Investigator

Contact: Email

Ann Cohen

Ann Cohen, Ph.D. - UPitt

Study Manager and Recruitment Team Leader. Bio: http://www.psychiatry.pitt.edu/person/ann-d-cohen-phd

Contact: Email

Yue-Fang Chang

Yue-Fang Chang, Ph.D. - UPitt

Statistics and Data Management Team Leader. Bio: http://www.neurosurgery.pitt.edu/person/yue-fang-chang

Ted Huppert

Ted Huppert, Ph.D. - UPitt

Beth Snitz

Beth Snitz, Ph.D. - UPitt

Study Protocol Overview

Research focus

  • Apply HCP protocol to 400 individuals age 50-89 years: 200 cognitively normal, 125 with Alzheimer’s Disease, 50 with Mild Cognitive Impairment, and 25 with subjective complaints of memory impairment.
  • Test the hypothesis that the expression of cognitive dysfunction in the elderly is the result of two independent processes — the first is the neuropathology associated with AD, and the second the neuropathological changes as a consequence of vascular disease. 

Data being collected

  • Standard HCP demographics
  • Imaging: The CBA project will collect imaging data for structural, functional (resting state and task) and diffusion using a Siemens 3T Prisma 64-channel. Functional MRI will include resting state, and the HCP memory and motor task-based fMRI protocols. Additional imaging studies include Amyloid imaging with Pittsburgh Compound B (PET-PIB) and Magnetoencephalography (task and task-free states) (MEG).  Of the 400 participants, 200 individuals (100 patients/100 controls) will undergo PET imaging for β amyloid and magnetoencephalography (using the HCP protocol). 100 of these individuals (25 SCI, 25 MCI, 50 Normal), half of whom (on a group-by-group basis) will have amyloid deposits.  These will be rescanned 24 months later. 
  • Clinical: The CBA will acquire critical data relative to both vascular risk and protective factors including: diet, exercise, body habitus, standardized blood pressures, inflammatory markers (CRP, IL-6, TNF-α), and metabolic data (glucose, HgA1c, lipids, homocysteine, Cystatin-c).   In collaboration with the University of Pittsburgh ADRC Genetics Core, we will obtain blood samples for processing for DNA analysis. We will genotype each individual participant for the APOE gene, as well as 20 previously identified candidate genes thought to increase risk for AD.  We will also look at inflammatory markers. 
  • Behavioral: Each of the study participants will complete the HCP-specified measures of sensation, motor functions, cognition, emotion, and personality traits.


Cohort Description

The study consists of 400 participants ranging in age from 50-89.  Of those, 200 will be cognitively normal, 125 will have Alzheimer’s Disease, 50 will have Mild Cognitive Impairment, and 25 will have complaints of memory impairment.


Data Release Plans

  • The first data release includes 80 participants.
  • The second data release includes 200 participants.

 The third data release includes 400 participants.


Keywords

Aging, Alzheimer’s, dementia, Pittsburgh Compound B, PET, PIB, Magnetoencephalography, MEG, cognitive impairment, cognitive dysfunction, memory, amyloid

Publications

  • Physical activity predicts reduced plasma β amyloid in the Cardiovascular Health Study.

    Chelsea M Stillman, Oscar L Lopez, James T Becker, Lewis H Kuller, Pankaj D Mehta, Russell P Tracy, Kirk I Erickson
    Show Summary

    Higher levels of physical activity (PA) reduce the risk of cognitive impairment, but the underlying mechanisms are unclear. Using longitudinal data from the Cardiovascular Health Study, we examined whether PA predicted plasma Aβ levels and risk for cognitive decline 9-13 years later.

  • Functional Connectivity Disruption in Subjective Cognitive Decline and Mild Cognitive Impairment: A Common Pattern of Alterations.

    David López-Sanz, Ricardo Bruña, Pilar Garcés, María Carmen Martín-Buro, Stefan Walter, María Luisa Delgado, Mercedes Montenegro, Ramón López Higes, Alberto Marcos, Fernando Maestú
    Show Summary

    Functional connectivity (FC) alterations represent a key feature in Alzheimer's Disease (AD) and provide a useful tool to characterize and predict the course of the disease. Those alterations have been also described in Mild Cognitive Impairment (MCI), a prodromal stage of AD. There is a growing interest in detecting AD pathology in the brain in the very early stages of the disorder. Subjective Cognitive Decline (SCD) could represent a preclinical asymptomatic stage of AD but very little is known about this population. In the present work we assessed whether FC disruptions are already present in this stage, and if they share any spatial distribution properties with MCI alterations (a condition known to be highly related to AD). To this end, we measured electromagnetic spontaneous activity with MEG in 39 healthy control elders, 41 elders with SCD and 51 MCI patients. The results showed FC alterations in both SCD and MCI compared to the healthy control group. Interestingly, both groups exhibited a very similar spatial pattern of altered links: a hyper-synchronized anterior network and a posterior network characterized by a decrease in FC. This decrease was more pronounced in the MCI group. These results highlight that elders with SCD present FC alterations. More importantly, those disruptions affected AD typically related areas and showed great overlap with the alterations exhibited by MCI patients. These results support the consideration of SCD as a preclinical stage of AD and may indicate that FC alterations appear very early in the course of the disease.

  • Comparison of group-level, source localized activity for simultaneous functional near-infrared spectroscopy-magnetoencephalography and simultaneous fNIRS-fMRI during parametric median nerve stimulation.

    Theodore Huppert, Jeff Barker, Benjamin Schmidt, Shawn Walls, Avniel Ghuman
    Neurophotonics, Feb 03, 2017 PMID: 28149919
    Show Summary

    Functional near-infrared spectroscopy (fNIRS) is a noninvasive neuroimaging technique, which uses light to measure changes in cerebral blood oxygenation through sensors placed on the surface of the scalp. We recorded concurrent fNIRS with magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) in order to investigate the group-level correspondence of these measures with source-localized fNIRS estimates. Healthy participants took part in both a concurrent fNIRS-MEG and fNIRS-fMRI neuroimaging session during two somatosensory stimulation tasks, a blocked design median nerve localizer and parametric pulsed-pair median nerve stimulation using interpulse intervals from 100 to 500 ms. We found the spatial correlation for estimated activation patterns from the somatosensory task was [Formula: see text], 0.57, and [Formula: see text] and the amplitude correlation was [Formula: see text], 0.52, and [Formula: see text] for fMRI-MEG, fMRI-fNIRS oxy-hemoglobin, and fMRI-fNIRS deoxy-hemoglobin signals, respectively. Taken together, these results show good correspondence among the fMRI, fNIRS, and MEG with the great majority of the difference across modalities being driven by lower sensitivity for deeper brain sources in MEG and fNIRS. These results provide an important validation of source-localized fNIRS in the context of concurrent multimodal imaging for future studies of the relationship between physiological effects in the human brain.

  • Association of Brain Amyloid-β With Slow Gait in Elderly Individuals Without Dementia: Influence of Cognition and Apolipoprotein E ε4 Genotype.

    Neelesh K Nadkarni, Subashan Perera, Beth E Snitz, Chester A Mathis, Julie Price, Jeff D Williamson, Steven T DeKosky, William E Klunk, Oscar L Lopez
    JAMA neurology, Nov 15, 2016 PMID: 27842173
    Show Summary

    Motor slowing appears in preclinical Alzheimer disease (AD), progresses with AD progression, and is associated with AD pathologic findings at autopsy. Whether amyloid-β (Aβ) is associated with gait speed in elderly individuals without dementia and whether cognition and apolipoprotein E ε4 (APOE ε4) influence this association remain unknown.

  • Distinct pathways for cognitive decline in the presence of Alzheimer's disease pathology or cerebrovascular disease.

    Ann D Cohen
  • Reduced binding of Pittsburgh Compound-B in areas of white matter hyperintensities.

    A E Goodheart, E Tamburo, D Minhas, H J Aizenstein, E McDade, B E Snitz, J C Price, C A Mathis, O L Lopez, W E Klunk, A D Cohen
    NeuroImage. Clinical, Nov 24, 2015 PMID: 26594630
    Show Summary

    The amyloid imaging agent, Pittsburgh Compound-B, binds with high affinity to β-amyloid (Aβ) in the brain, and it is well established that PiB also shows non-specific retention in white matter (WM). However, little is known about retention of PiB in areas of white matter hyperintensities (WMH), abnormalities commonly seen in older adults. Further, it is hypothesized that WMH are related to both cognitive dysfunction and Aβ deposition. The goal of the present study was to explore PiB retention in both normal-appearing WM (NAWM) and WMH in a group of elderly, cognitively normal individuals. In a group of cognitively normal elderly (n = 64; 86.5 ± 2.6 years) two analyses were applied: (1) ROIs were placed over periventricular areas in which WMH caps are commonly seen on all subjects, regardless of WMH burden or size. (2) Subject-specific maps of NAWM and WMH were co-registered with the PiB-PET images and mean SUVR values were calculated in these NAWM and WMH maps. PiB retention was significantly reduced in the ROIs of subjects with high WMH compared to subjects with low WMH. Additionally, in subjects with high WMH, there was significantly lower PiB retention in subject-specific maps of WMH compared to NAWM, which was not observed in subjects with low WMH, likely because of the small size of WMH maps in this group. These data suggest that WM in areas of WMH binds PiB less effectively than does normal WM. Further exploration of this phenomenon may lead to insights about the molecular basis of the non-specific retention of amyloid tracers in white matter.

  • Do Subjective Memory Complaints Lead or Follow Objective Cognitive Change? A Five-Year Population Study of Temporal Influence.

    Beth E Snitz, Brent J Small, Tianxiu Wang, Chung-Chou H Chang, Tiffany F Hughes, Mary Ganguli
    Show Summary

    The relationship between subjective memory complaints (SM) and objective memory (OM) performance in aging has been variably characterized in a substantial literature, to date. In particular, cross-sectional studies often observe weak or no associations. We investigated whether subjective memory complaints and objectively measured cognition influence each other over time, and if so, which is the stronger pathway of change-objective to subjective, or subjective to objective-or whether they are both important. Using bivariate latent change score modeling in data from a population study (N=1980) over 5 annual assessment cycles, we tested four corresponding hypotheses: (1) no coupling between SM and OM over time; (2) SM as leading indicator of change in OM; (3) OM as leading indicator of change in SM; (4) dual coupling over time, with both SM and OM leading subsequent change in the other. We also extended objective cognition to two other domains, language and executive functions. The dual-coupling models best fit the data for all three objective cognitive domains. The SM-OM temporal dynamics differ qualitatively compared to other domains, potentially reflecting changes in insight and self-awareness specific to memory impairment. Subjective memory and objective cognition reciprocally influence each other over time. The temporal dynamics between subjective and objective cognition in aging are nuanced, and must be carefully disentangled to shed light on the underlying processes.

  • Amyloid-β Imaging in Older Adults Presenting to a Memory Clinic with Subjective Cognitive Decline: A Pilot Study.

    Beth E Snitz, Oscar L Lopez, Eric McDade, James T Becker, Ann D Cohen, Julie C Price, Chester A Mathis, William E Klunk
    Show Summary

    Subjective cognitive decline (SCD) in otherwise normal aging may be identified via symptom inventories in a research setting ('questionnaire-discovered complaints') or via patients seeking evaluation/services in a clinical setting ('presenting complainers'). Most studies of SCD and amyloid-β (Aβ) imaging to date have used the former approach, with inconsistent results.

  • Subjective Cognitive Complaints, Personality and Brain Amyloid-beta in Cognitively Normal Older Adults.

    Beth E Snitz, Lisa A Weissfeld, Ann D Cohen, Oscar L Lopez, Robert D Nebes, Howard J Aizenstein, Eric McDade, Julie C Price, Chester A Mathis, William E Klunk
    Show Summary

    Subjective cognitive complaints in otherwise normal aging are common but may be associated with preclinical Alzheimer disease in some individuals. Little is known about who is mostly likely to show associations between cognitive complaints and preclinical Alzheimer pathology. We sought to demonstrate associations between subjective complaints and brain amyloid-β in cognitively normal older adults; and to explore personality factors as potential moderators of this association.

  • Voxel Level Survival Analysis of Grey Matter Volume and Incident Mild Cognitive Impairment or Alzheimer's Disease.

    Lubov E Zeifman, William F Eddy, Oscar L Lopez, Lewis H Kuller, Cyrus Raji, Paul M Thompson, James T Becker
    Show Summary

    The purpose of this study was to identify, at the voxel level, brain regions associated with the time to develop mild cognitive impairment (MCI) or Alzheimer's disease (AD) from normal cognition. We analyzed incident MCI (n = 58) or AD (n = 151) in 292 cognitively normal participants in the Cardiovascular Health Study-Cognition Study (mean age = 79.2 ± 3.6 years). We used segmented, modulated grey matter maps from 3D (spoiled gradient echo) MRI scans obtained in 1998/99 (with clinical follow-up through 2012) that were smoothed with a 3-D 4 mm Gaussian filter. We fit approximately 1.92 million voxel-level Cox proportional hazard models to examine the grey matter volume effect on time to event, adjusting for age, sex, and diabetes. We used the significance threshold of p <  0.005 with contiguity threshold of at least 68 voxels (false detection probability <2.5×10 -8). Areas within the mesial temporal lobe (MTL), anterior temporal lobe, hippocampus, and posterior cingulate gyrus were associated with time to MCI or AD. The presence of white matter lesions (a marker of small vessel disease in the brain) was associated with the volumes of the MTL and precuneus; MRI-identified infarcts also predicted MTL volume. These findings are important because we identified critical brain regions that predict a person's increased likelihood of developing MCI or AD over a decade prior to the onset of clinical symptoms; these critical brain regions were themselves affected by the presence of vascular disease.

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