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J Psychiatr Res. 2020 Apr;123:81-88. doi: 10.1016/j.jpsychires.2020.01.018. Epub 2020 Jan 30.

Disrupted functional connectivity of the locus coeruleus in healthy adults with parental history of Alzheimer's disease.

Author information

1
Bellvitge Biomedical Research Institute-IDIBELL, Department of Psychiatry, Bellvitge University Hospital, Feixa Llarga S/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain; Department of Clinical Sciences, Bellvitge Campus, Barcelona University, Faculty of Medicine, Feixa Llarga, S/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain; Network Center for Biomedical Research on Mental Health (CIBERSAM), Av. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain. Electronic address: idelcerro@idibell.cat.
2
Grupo de Investigación en Neurociencias Aplicadas a Las Alteraciones de La Conducta (INAAC), FLENI, Montañeses, 2325, Ciudad Autónoma de Buenos Aires, Argentina; Department of Physics, University of Buenos Aires. Pabellón I, Ciudad Universitaria, 1428, Ciudad Autónoma de Buenos Aires, Argentina; National Council for Scientific and Technological Research (CONICET), Godoy Cruz, 2290, Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: mvillarreal@fleni.org.ar.
3
Grupo de Investigación en Neurociencias Aplicadas a Las Alteraciones de La Conducta (INAAC), FLENI, Montañeses, 2325, Ciudad Autónoma de Buenos Aires, Argentina; National Council for Scientific and Technological Research (CONICET), Godoy Cruz, 2290, Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: carolina.abulafia@gmail.com.
4
Grupo de Investigación en Neurociencias Aplicadas a Las Alteraciones de La Conducta (INAAC), FLENI, Montañeses, 2325, Ciudad Autónoma de Buenos Aires, Argentina; National Council for Scientific and Technological Research (CONICET), Godoy Cruz, 2290, Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: bmduarteabritta@gmail.com.
5
Grupo de Investigación en Neurociencias Aplicadas a Las Alteraciones de La Conducta (INAAC), FLENI, Montañeses, 2325, Ciudad Autónoma de Buenos Aires, Argentina; National Council for Scientific and Technological Research (CONICET), Godoy Cruz, 2290, Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: stellamarissanchez89@gmail.com.
6
Grupo de Investigación en Neurociencias Aplicadas a Las Alteraciones de La Conducta (INAAC), FLENI, Montañeses, 2325, Ciudad Autónoma de Buenos Aires, Argentina; National Council for Scientific and Technological Research (CONICET), Godoy Cruz, 2290, Ciudad Autónoma de Buenos Aires, Argentina; Department of Psychiatry, FLENI and Department of Psychiatry and Mental Health, School of Medicine, University of Buenos Aires, Montañeses, 2325, Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: mariananaircastro@gmail.com.
7
Grupo de Investigación en Neurociencias Aplicadas a Las Alteraciones de La Conducta (INAAC), FLENI, Montañeses, 2325, Ciudad Autónoma de Buenos Aires, Argentina; National Council for Scientific and Technological Research (CONICET), Godoy Cruz, 2290, Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: hbocaccio@gmail.com.
8
Department of Pathology and Experimental Therapeutics, Institute of Neurosciences, University of Barcelona, Facultad de Medicina y Ciencias de La Salud, Campus de Bellvitge, Pavelló de Govern, Feixa Llarga, S/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain; Bellvitge Biomedical Research Institute-IDIBELL, Department of Pathologic Anatomy, Bellvitge University Hospital, Feixa Llarga S/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain; Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Valderrebollo, 5, 28031, Madrid, Spain. Electronic address: 8082ifa@gmail.com.
9
Bellvitge Biomedical Research Institute-IDIBELL, Department of Psychiatry, Bellvitge University Hospital, Feixa Llarga S/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain; Department of Clinical Sciences, Bellvitge Campus, Barcelona University, Faculty of Medicine, Feixa Llarga, S/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain; Network Center for Biomedical Research on Mental Health (CIBERSAM), Av. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain. Electronic address: jmenchon@bellvitgehospital.cat.
10
National Council for Scientific and Technological Research (CONICET), Godoy Cruz, 2290, Ciudad Autónoma de Buenos Aires, Argentina; Department of Molecular Biology, FLENI, Montañeses, 2325, Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: gsevlever@fleni.org.ar.
11
Department of Psychiatry, Dell University of Texas at Austin and Institute of Early Life Adversity Research, Dell Medical School, The University of Texas, Austin, TX, 78712, USA. Electronic address: cnemeroff@austin.utexas.edu.
12
Bellvitge Biomedical Research Institute-IDIBELL, Department of Psychiatry, Bellvitge University Hospital, Feixa Llarga S/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain; Network Center for Biomedical Research on Mental Health (CIBERSAM), Av. Monforte de Lemos, 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain; Department of Psychobiology and Methodology in Health Sciences, Universitat Autònoma de Barcelona, Carrer Fortuna, Edifici B, 08193, Bellaterra (Cerdanyola Del Vallès), Barcelona, Spain. Electronic address: csoriano@idibell.cat.
13
Grupo de Investigación en Neurociencias Aplicadas a Las Alteraciones de La Conducta (INAAC), FLENI, Montañeses, 2325, Ciudad Autónoma de Buenos Aires, Argentina; National Council for Scientific and Technological Research (CONICET), Godoy Cruz, 2290, Ciudad Autónoma de Buenos Aires, Argentina; Department of Psychiatry, FLENI and Department of Psychiatry and Mental Health, School of Medicine, University of Buenos Aires, Montañeses, 2325, Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: sguinjoan@fleni.org.ar.

Abstract

Prevention and early treatment strategies for Alzheimer's disease (AD) are hampered by the lack of research biomarkers. Neuropathological changes in the Locus Coeruleus (LC) are detected early in AD, and noradrenaline plays a neuroprotective role in LC projecting areas. We assessed functional connectivity (FC) of the brainstem in asymptomatic individuals at familial risk for AD hypothesizing that FC of the LC will be decreased in relation to not-at-risk individuals. Thirty-one offspring of patients with late-onset AD (O-LOAD) (22 females; mean age ± SD = 50.36 ± 8.32) and 28 healthy controls (HC) (20 females; mean age ± SD = 53.90 ± 8.44) underwent a neurocognitive evaluation and a resting-state functional magnetic resonance imaging acquisition. In FC analyses we evaluated whole-brain global connectivity of the brainstem area, and subsequently assessed seed-to-voxel FC patterns from regions showing between-group differences. O-LOAD individuals scored worse in neurocognitive measures of memory and overall functioning (pFDR<0.05). In imaging analyses, we observed that O-LOAD individuals showed decreased global connectivity in a cluster encompassing the left LC (peak = -4, -34, -32, pTFCE<0.05). Seed-to-voxel analyses revealed that this finding was largely explained by decreased connectivity between the LC and the cerebellar cortex. Moreover, FC between the LC and the left cerebellum correlated positively with delayed recall scores. FC between the LC and the cerebellar cortex is decreased in the healthy offspring of patients with LOAD, such connectivity measurements being associated with delayed memory scores. The assessment of FC between the LC and the cerebellum may serve as a biomarker of AD vulnerability.

KEYWORDS:

Alzheimer's disease offspring; Biomarkers; Cerebellum; Functional connectivity; Locus coeruleus; Neurodegeneration

Conflict of interest statement

Declaration of competing interest Dr. Charles B. Nemeroff's disclosures are as follows: Consulting (last three years): Xhale, Takeda, Taisho Pharmaceutical Inc., Prismic Pharmaceuticals, Bracket (Clintara), Total Pain Solutions (TPS), Gerson Lehrman Group (GLG) Healthcare & Biomedical Council, Fortress Biotech, Sunovion Pharmaceuticals Inc., Sumitomo Dainippon Pharma, Janssen Research & Development LLC, Magstim, Inc., Navitor Pharmaceuticals, Inc., TC MSO, Inc., Intra-Cellular Therapies, Inc. Stockholder: Xhale, Celgene, Seattle Genetics, Abbvie, OPKO Health, Inc., Network Life Sciences Inc., Antares, BI Gen Holdings, Inc, Corcept Therapeutics Pharmaceuticals Company, TC MSO, In., Trends in Pharma Development, LLC. Advisory boards: American Foundation for Suicide Prevention (AFSP), Brain and Behavior Research Foundation (BBRF), Xhale, Anxiety Disorders Association of America (ADAA), Skyland Trail, Bracket (Clintara), Laureate Institute for Brain Research (LIBR), Inc. Board of directors: AFSP, Gratitude America and ADAA. Income sources or equity of $10 000 or more from: American Psychiatric Publishing, Xhale, Bracket (Clintara), CME Outfitters, Takeda, Intra-Cellular Therapies, Inc., Magstim and EMA Wellness. Patents: Method and devices for transdermal delivery of lithium (US 6 375 990 B1). Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7 148 027 B2). Compounds, compositions, methods of synthesis, and methods of treatment (CRF receptor binding ligand) (US 8 551 996 B2). All other authors have nothing to disclose nor have any financial relationships with commercial interests.

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