CRHD The Structural & Functional Connectome across AD Subtypes

Study Overview

This study explores Alzheimer’s disease (AD), specifically those of Mexican Mestizo origin.  AD can be divided into subtypes by genetic origins, each of which may have distinct pathogenetic cascades and therefore may respond differentially to treatments. 

By applying the HCP protocol to persons at-risk for fully-penetrant autosomal dominant AD (ADAD due to either the A431E PSEN1 or V717I APP mutations) in conjunction with positron emission tomography (PET) imaging of tau using the novel ligand 18F-T807, we will be able to test the hypothesis that tau pathology spreads in a trans-synaptic manner along definable neural pathways.  Applying the HCP protocol to those of Mexican descent will provide the opportunity to test the hypothesis of transynaptic spread of tau in the etiology of AD and provide the opportunity to differentiate pathological processes in subtypes of AD and therefore inform approaches to treatment.  As PSEN1-related AD can present with spastic paraparesis, an easily assessed phenotype, we will be able to relate the neurophysiological parameters of central nervous system conduction time to connectivity measures in the HCP. 

Project Timespan: Sept. 30, 2015 - Sept. 29, 2019

Investigators

John Ringman

John Ringman, M.D. - USC Principal Investigator

Contact: Email

Study Protocol Overview

Data being collected
Participants will be evaluated at the University of Southern California during one visit. 

  • Standard HCP demographics.
  • Imaging: MR data collection will be conducted on a 3T Siemens Prisma.  The imaging modalities include structural, functional (both resting state and task), and diffusion.  The HCP LifeSpan protocol has been augmented with the following sequences:   (a) Pseudocontinuous ASL (pCASL), (b) The HCP tfMRI motor strip mapping sequence, (c) The HCP tfMRI language sequence, (d) A Susceptibility Weighted Imaging (SWI) sequence.  PET imaging will also be used.
  • Clinical:  A number of measures unique to the AD study will be collected for cognition, sleep, spasticity, gene mutations and genotyping, acculturation scale, and other health measures.
  • Behavioral: In addition to the NIH Toolbox and non-NIH Toolbox measures in the HCP LifeSpan protocol, a number of behavioral measures will be implemented, such as cognitive, sleep, spasticity, genotyping, and acculturation scale. 


Cohort Description
The study includes 200 participants between the ages of 18 and 80 years old, primarily of Mexican descent.  Control participants will be either persons at-risk for autosomal dominant Alzheimer’s disease mutations who are negative on genetic testing, or participants who are cognitively normal elderly persons of Mexican descent.


Data Release Plans

  • The first data release includes 14 participants.
  • The second data release includes 76 participants.
  • The third data release includes 138 participants.
  • The fourth data release includes 200 participants.


Keywords 

Alzheimer's Disease; APP gene; autosomal dominant mutation; Dementia; Mexican; Nerve Degeneration

Publications

  • Widespread white matter and conduction defects in PSEN1-related spastic paraparesis.

    Steffan K Soosman, Nelly Joseph-Mathurin, Meredith N Braskie, Yvette M Bordelon, David Wharton, Maria Casado, Giovanni Coppola, Holly McCallum, Marc Nuwer, Pedro Coutin-Churchman, Liana G Apostolova, Tammie Benzinger, John M Ringman
    Neurobiology of aging, Oct 25, 2016 PMID: 27614114
    Show Summary

    The mechanisms underlying presenilin 1 (PSEN1) mutation-associated spastic paraparesis (SP) are not clear. We compared diffusion and volumetric magnetic resonance measures between 3 persons with SP associated with the A431E mutation and 7 symptomatic persons with PSEN1 mutations without SP matched for symptom duration. We performed amyloid imaging and central motor and somatosensory conduction studies in 1 subject with SP. We found decreases in fractional anisotropy and increases in mean diffusivity in widespread white-matter areas including the corpus callosum, occipital, parietal, and frontal lobes in PSEN1 mutation carriers with SP. Volumetric measures were not different, and amyloid imaging showed low signal in sensorimotor cortex and other areas in a single subject with SP. Electrophysiological studies demonstrated both slowed motor and sensory conduction in the lower extremities in this same subject. Our results suggest that SP in carriers of the A431E PSEN1 mutation is a manifestation of widespread white-matter abnormalities not confined to the corticospinal tract that is at most indirectly related to the mutation's effect on amyloid precursor protein processing and amyloid deposition.

  • Are Late-Onset Autosomal Dominant and Sporadic Alzheimer Disease "Separate but Equal"?

    John M Ringman
    JAMA neurology, Jul 26, 2016 PMID: 27455517
  • Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database.

    John M Ringman, Sarah Monsell, Denise W Ng, Yan Zhou, Andy Nguyen, Giovanni Coppola, Victoria Van Berlo, Mario F Mendez, Spencer Tung, Sandra Weintraub, Marek-Marsel Mesulam, Eileen H Bigio, Darren R Gitelman, Amanda O Fisher-Hubbard, Roger L Albin, Harry V Vinters
    Show Summary

    Alzheimer disease (AD) represents a genetically heterogeneous entity. To elucidate neuropathologic features of autosomal dominant AD ([ADAD] due to PSEN1, APP, or PSEN2 mutations), we compared hallmark AD pathologic findings in 60 cases of ADAD and 120 cases of sporadic AD matched for sex, race, ethnicity, and disease duration. Greater degrees of neuritic plaque and neurofibrillary tangle formation and cerebral amyloid angiopathy (CAA) were found in ADAD (p values < 0.01). Moderate to severe CAA was more prevalent in ADAD (63.3% vs. 39.2%, p = 0.003), and persons with PSEN1 mutations beyond codon 200 had higher average Braak scores and severity and prevalence of CAA than those with mutations before codon 200. Lewy body pathology was less extensive in ADAD but was present in 27.1% of cases. We also describe a novel pathogenic PSEN1 mutation (P267A). The finding of more severe neurofibrillary pathology and CAA in ADAD, particularly in carriers of PSEN1 mutations beyond codon 200, warrants consideration when designing trials to treat or prevent ADAD. The finding of Lewy body pathology in a substantial minority of ADAD cases supports the assertion that development of Lewy bodies may be in part driven by abnormal β-amyloid protein precursor processing.

  • Assessing intracranial vascular compliance using dynamic arterial spin labeling.

    Lirong Yan, Collin Y Liu, Robert X Smith, Mayank Jog, Michael Langham, Kate Krasileva, Yufen Chen, John M Ringman, Danny J J Wang
    NeuroImage, Sep 15, 2015 PMID: 26364865
    Show Summary

    Vascular compliance (VC) is an important marker for a number of cardiovascular diseases and dementia, which is typically assessed in the central and peripheral arteries indirectly by quantifying pulse wave velocity (PWV), and/or pulse pressure waveform. To date, very few methods are available for the quantification of intracranial VC. In the present study, a novel MRI technique for in-vivo assessment of intracranial VC was introduced, where dynamic arterial spin labeling (ASL) scans were synchronized with the systolic and diastolic phases of the cardiac cycle. VC is defined as the ratio of change in arterial cerebral blood volume (ΔCBV) and change in arterial pressure (ΔBP). Intracranial VC was assessed in different vascular components using the proposed dynamic ASL method. Our results show that VC mainly occurs in large arteries, and gradually decreases in small arteries and arterioles. The comparison of intracranial VC between young and elderly subjects shows that aging is accompanied by a reduction of intracranial VC, in good agreement with the literature. Furthermore, a positive association between intracranial VC and cerebral perfusion measured using pseudo-continuous ASL with 3D GRASE MRI was observed independent of aging effects, suggesting loss of VC is associated with a decline in perfusion. Finally, a significant positive correlation between intracranial and central (aortic arch) VC was observed using an ungated phase-contrast 1D projection PWV technique. The proposed dynamic ASL method offers a promising approach for assessing intracranial VC in a range of cardiovascular diseases and dementia.

  • Use of the MoCA in Detecting Early Alzheimer's Disease in a Spanish-Speaking Population with Varied Levels of Education.

    Yan Zhou, Freddy Ortiz, Christopher Nuñez, David Elashoff, Ellen Woo, Liana G Apostolova, Sheldon Wolf, Maria Casado, Nenette Caceres, Hemali Panchal, John M Ringman
    Show Summary

    Performance on the Montreal Cognitive Assessment (MoCA) has been demonstrated to be dependent on the educational level. The purpose of this study was to identify how to best adjust MoCA scores and to identify MoCA items most sensitive to cognitive decline in incipient Alzheimer's disease (AD) in a Spanish-speaking population with varied levels of education.

  • Early behavioural changes in familial Alzheimer's disease in the Dominantly Inherited Alzheimer Network.

    John M Ringman, Li-Jung Liang, Yan Zhou, Sitaram Vangala, Edmond Teng, Sarah Kremen, David Wharton, Alison Goate, Daniel S Marcus, Martin Farlow, Bernardino Ghetti, Eric McDade, Colin L Masters, Richard P Mayeux, Martin Rossor, Stephen Salloway, Peter R Schofield, Jeffrey L Cummings, Virginia Buckles, Randall Bateman, John C Morris, Dominantly Inherited Alzheimer Network
    Show Summary

    Prior studies indicate psychiatric symptoms such as depression, apathy and anxiety are risk factors for or prodromal symptoms of incipient Alzheimer's disease. The study of persons at 50% risk for inheriting autosomal dominant Alzheimer's disease mutations allows characterization of these symptoms before progressive decline in a population destined to develop illness. We sought to characterize early behavioural features in carriers of autosomal dominant Alzheimer's disease mutations. Two hundred and sixty-one persons unaware of their mutation status enrolled in the Dominantly Inherited Alzheimer Network, a study of persons with or at-risk for autosomal dominant Alzheimer's disease, were evaluated with the Neuropsychiatric Inventory-Questionnaire, the 15-item Geriatric Depression Scale and the Clinical Dementia Rating Scale (CDR). Ninety-seven asymptomatic (CDR = 0), 25 mildly symptomatic (CDR = 0.5), and 33 overtly affected (CDR > 0.5) autosomal dominant Alzheimer's disease mutation carriers were compared to 106 non-carriers with regard to frequency of behavioural symptoms on the Neuropsychiatric Inventory-Questionnaire and severity of depressive symptoms on the Geriatric Depression Scale using generalized linear regression models with appropriate distributions and link functions. Results from the adjusted analyses indicated that depressive symptoms on the Neuropsychiatric Inventory-Questionnaire were less common in cognitively asymptomatic mutation carriers than in non-carriers (5% versus 17%, P = 0.014) and the odds of experiencing at least one behavioural sign in cognitively asymptomatic mutation carriers was lower than in non-carriers (odds ratio = 0.50, 95% confidence interval: 0.26-0.98, P = 0.042). Depression (56% versus 17%, P = 0.0003), apathy (40% versus 4%, P < 0.0001), disinhibition (16% versus 2%, P = 0.009), irritability (48% versus 9%, P = 0.0001), sleep changes (28% versus 7%, P = 0.003), and agitation (24% versus 6%, P = 0.008) were more common and the degree of self-rated depression more severe (mean Geriatric Depression Scale score of 2.8 versus 1.4, P = 0.006) in mildly symptomatic mutation carriers relative to non-carriers. Anxiety, appetite changes, delusions, and repetitive motor activity were additionally more common in overtly impaired mutation carriers. Similar to studies of late-onset Alzheimer's disease, we demonstrated increased rates of depression, apathy, and other behavioural symptoms in the mildly symptomatic, prodromal phase of autosomal dominant Alzheimer's disease that increased with disease severity. We did not identify any increased psychopathology in mutation carriers over non-carriers during the presymptomatic stage, suggesting these symptoms result when a threshold of neurodegeneration is reached rather than as life-long qualities. Unexpectedly, we found lower rates of depressive symptoms in cognitively asymptomatic mutation carriers.

  • Genetic heterogeneity in Alzheimer disease and implications for treatment strategies.

    John M Ringman, Alison Goate, Colin L Masters, Nigel J Cairns, Adrian Danek, Neill Graff-Radford, Bernardino Ghetti, John C Morris, Dominantly Inherited Alzheimer Network
    Show Summary

    Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer's disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses.

  • Younger age of dementia diagnosis in a Hispanic population in southern California.

    L Jaime Fitten, Freddy Ortiz, Lynn Fairbanks, George Bartzokis, Po Lu, Eric Klein, Giovanni Coppola, John Ringman
    Show Summary

    Prior studies of US Hispanics, largely performed on the East Coast, have found a younger age of dementia onset than in White non-Hispanics. We performed a cross-sectional study to examine clinical and sociodemographic variables associated with age of dementia diagnosis in older Hispanics and White, non-Hispanics in southern California.

Contact This Study

Please contact John Ringman, M.D. for more information regarding this study.

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