Connectomic Imaging in Familial & Sporadic Frontotemporal Degeneration

Study Overview

Frontotemporal Dementia Connectomics (FTDConn) - Neurodegenerative disease is a major public health problem. Frontotemporal degeneration (FTD) is a clinical neurodegenerative condition that affects both gray matter (GM) and white matter (WM) and causes a network disorder. 

FTD is an excellent model for directly imaging the neurobiology of neurodegeneration because the associated pathology involves a monoproteinopathy in each patient - either frontotemporal lobar degeneration (FTLD) due to tau (FTLD-tau) or to TAR DNA binding protein of ~43kD (FTLD-TDP). We use a connectomic approach to identify FTLD-tau and FTLD-TDP in vivo. This is timely because of the pressing needs for accurate antemortem diagnosis, for discovery of disease-modifying agents, for biomarkers to gauge response during treatment trials, and for elucidating mechanisms of disease progression even at the preclinical stage. 

About 25% of cases have familial FTD (fFTD) due to a small set of mutations causing one of these pathologies. The remaining 75% of cases have sporadic FTD (sFTD) with no definitive biomarkers for FTLD-tau or FTLD-TDP pathology. Multimodal structural MRI (sMRI) of GM disease and diffusion MRI (dMRI) of WM disease appears to identify vulnerable networks in FTLD-tau and FTLD-TDP. A five-site consortium, including Mayo Clinic, MGH/Harvard, Northwestern University, University of California in San Francisco, and University of Pennsylvania, is acquiring HCP imaging in FTD, including sMRI, dMRI, resting BOLD MRI (rs-fMRI), task-based functional MRI (tfMRI) and arterial spin labeling (ASL) in presymptomatic and symptomatic fFTD associated with FTLD-tau or FTLD-TDP, and in sFTD with specific phenotypes highly associated with FTLD-tau or FTLD-TDP. Connectomic imaging will be integrated with NIH-funded registries that acquire clinical, cognitive, genetic and biofluid data. We are also acquiring longitudinal data to assess competing hypotheses about mechanisms of disease spread in presymptomatic and symptomatic FTD. Graph theoretic and multimodal network analyses is being used to show disease spreading locally to adjacent brain regions, affecting different networks in FTLD-tau or FTLD-TDP.

Investigators

Murray Grossman

Murray Grossman, M.D., Ed.D. - UPENN Principal Investigator

Contact: Email

Corey McMillan

Corey McMillan, PhD - UPENN Principal Investigator

Contact: Email

Bradley Boeve

Bradley Boeve, M.D. - Mayo Clinic

Bradford Dickerson

Bradford Dickerson, M.D. - MGH

Maria Luisa Gorno-Tempini

Maria Luisa Gorno-Tempini, M.D., Ph.D. - UCSF

Emily Rogalski

Emily Rogalski, Ph.D. - Northwestern

Daniel Wakeman

Daniel Wakeman, Ph.D. - UPENN

Contact: Email

Study Protocol Overview

Data being collected

Data will be collected at the five sites. all sites are using a Siemens Prisma 3T scanner.

  • Standard HCP demographics.
  • Imaging: The imaging modalities are structural, diffusion, and functional (both resting state and task) with the following tasks:  working memory and gambling.
  • Clinical: Genotyping, Cytokine measurement, cerebrospinal fluid, autopsy, semi-quantitative and quantitative histopathology.
  • Behavioral: NIH Toolbox measures of the HCP LifeSpan protocol, UDS-3, FTLD-NACC batteries, neuropsychological survey and database.


Cohort Description

The study includes of 200 participants age 30 years or more, with a mean age around 55-60 years of age.  The FTDConn will collect 40 healthy controls (10 per site), including 20 non-mutation-carrying siblings of familial FTD participants and 20 siblings of sporadic FTD participants.


Data Release Plans

  • The first data release includes 200 participants
  • The second data release includes 200 participants, first follow up
  • The third data release includes 200 participants, second follow up


Keywords

Frontotemporal dementia, connectomics, FTD, neurodegenerative, degeneration

Publications

  • Asymmetry of cortical decline in subtypes of primary progressive aphasia.

    Emily Rogalski, Derin Cobia, Adam Martersteck, Alfred Rademaker, Christina Wieneke, Sandra Weintraub, M-Marsel Mesulam
    Neurology, Aug 29, 2014 PMID: 25165386
    Show Summary

    The aim of this study was to provide quantitative measures of changes in cortical atrophy over a 2-year period associated with 3 subtypes of primary progressive aphasia (PPA) using whole-brain vertex-wise and region-of-interest (ROI) neuroimaging methods. The purpose was to quantitate disease progression, establish an empirical basis for clinical expectations, and provide outcome measures for therapeutic trials.

  • Genetic and neuroanatomic associations in sporadic frontotemporal lobar degeneration.

    Corey T McMillan, Jon B Toledo, Brian B Avants, Philip A Cook, Elisabeth M Wood, Eunran Suh, David J Irwin, John Powers, Christopher Olm, Lauren Elman, Leo McCluskey, Gerard D Schellenberg, Virginia M-Y Lee, John Q Trojanowski, Vivianna M Van Deerlin, Murray Grossman
    Neurobiology of aging, Dec 31, 2013 PMID: 24373676
    Show Summary

    Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that are sensitive for tau or TDP-43 pathology in frontotemporal lobar degeneration (FTLD). Neuroimaging analyses have revealed distinct distributions of disease in FTLD patients with genetic mutations. However, genetic influences on neuroanatomic structure in sporadic FTLD have not been assessed. In this report, we use novel multivariate tools, Eigenanatomy, and sparse canonical correlation analysis to identify associations between SNPs and neuroanatomic structure in sporadic FTLD. Magnetic resonance imaging analyses revealed that rs8070723 (MAPT) was associated with gray matter variance in the temporal cortex. Diffusion tensor imaging analyses revealed that rs1768208 (MOBP), rs646776 (near SORT1), and rs5848 (PGRN) were associated with white matter variance in the midbrain and superior longitudinal fasciculus. In an independent autopsy series, we observed that rs8070723 and rs1768208 conferred significant risk of tau pathology relative to TDP-43, and rs646776 conferred increased risk of TDP-43 pathology relative to tau. Identified brain regions and SNPs may help provide an in vivo screen for underlying pathology in FTLD and contribute to our understanding of sporadic FTLD.

  • In vivo signatures of nonfluent/agrammatic primary progressive aphasia caused by FTLD pathology.

    Francesca Caso, Maria Luisa Mandelli, Maya Henry, Benno Gesierich, Brianne M Bettcher, Jennifer Ogar, Massimo Filippi, Giancarlo Comi, Giuseppe Magnani, Manu Sidhu, John Q Trojanowski, Eric J Huang, Lea T Grinberg, Bruce L Miller, Nina Dronkers, William W Seeley, Maria Luisa Gorno-Tempini
    Neurology, Dec 20, 2013 PMID: 24353332
    Show Summary

    To identify early cognitive and neuroimaging features of sporadic nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) caused by frontotemporal lobar degeneration (FTLD) subtypes.

  • Intrinsic amygdala-cortical functional connectivity predicts social network size in humans.

    Kevin C Bickart, Mark C Hollenbeck, Lisa Feldman Barrett, Bradford C Dickerson
    Show Summary

    Using resting-state functional magnetic resonance imaging data from two independent samples of healthy adults, we parsed the amygdala's intrinsic connectivity into three partially distinct large-scale networks that strongly resemble the known anatomical organization of amygdala connectivity in rodents and monkeys. Moreover, in a third independent sample, we discovered that people who fostered and maintained larger and more complex social networks not only had larger amygdala volumes, but also amygdalae with stronger intrinsic connectivity within two of these networks: one putatively subserving perceptual abilities and one subserving affiliative behaviors. Our findings were anatomically specific to amygdalar circuitry in that individual differences in social network size and complexity could not be explained by the strength of intrinsic connectivity between nodes within two networks that do not typically involve the amygdala (i.e., the mentalizing and mirror networks), and were behaviorally specific in that amygdala connectivity did not correlate with other self-report measures of sociality.

  • Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72.

    Bradley F Boeve, Kevin B Boylan, Neill R Graff-Radford, Mariely DeJesus-Hernandez, David S Knopman, Otto Pedraza, Prashanthi Vemuri, David Jones, Val Lowe, Melissa E Murray, Dennis W Dickson, Keith A Josephs, Beth K Rush, Mary M Machulda, Julie A Fields, Tanis J Ferman, Matthew Baker, Nicola J Rutherford, Jennifer Adamson, Zbigniew K Wszolek, Anahita Adeli, Rodolfo Savica, Brendon Boot, Karen M Kuntz, Ralitza Gavrilova, Andrew Reeves, Jennifer Whitwell, Kejal Kantarci, Clifford R Jack, Joseph E Parisi, John A Lucas, Ronald C Petersen, Rosa Rademakers
    Show Summary

    Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.

Data Use Terms

When users request access to the NIMH Data Archive (NDA), they sign the NDA Data Use Certification (DUC) under which the data is shared. This DUC is usually submitted to the NDA electronically, but this printable version can also be submitted to NDAhelp@mail.nih.gov.

More information on obtaining NDA access is available in the Data Access and Download Instructions.

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