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1. Striatal Dopaminergic Deficit and Sleep in Idiopathic Rapid Eye Movement Behaviour Disorder: An Explorative Study

Author

Wasserman D, Bindman D, Nesbitt AD, Cash D, Milosevic M, Francis PT, Chaudhuri KR, Leschziner GD, Ferini-Strambi L, Ballard C, Eccles A, and Rosenzweig I

Subjects
isolated rapid eye movement behaviour disorder, polysomnography, sleep architecture, striatum, striatal dopamine transporter uptake tracer signalling imaging, datscan., Psychiatry, RC435-571, Neurophysiology and neuropsychology, QP351-495
Abstract

Danielle Wasserman,1,2,* Dorothea Bindman,1,* Alexander D Nesbitt,1– 3 Diana Cash,4 Milan Milosevic,5 Paul T Francis,6 K Ray Chaudhuri,7 Guy D Leschziner,1,2 Luigi Ferini-Strambi,8 Clive Ballard,9 Amy Eccles,10 Ivana Rosenzweig1,2 1Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, UK; 2Sleep Disorders Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 3Headache Group, Department of Clinical Neurosciences, King’s College Hospital NHS Foundation Trust, London, UK; 4BRAIN, Department of Neuroimaging, King’s College London, London, UK; 5School of Public Health “Andrija Stampar“, University of Zagreb School of Medicine, Zagreb, Croatia; 6Wolfson Centre for Age-Related Diseases, King’s College London, London, UK; 7Movement Disorders Unit, King’s College Hospital, Department of Clinical and Basic Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, Parkinson Foundation Centre of Excellence, King’s College London, London, UK; 8Sleep Disorders Center, Department of Clinical Neurosciences, Università Vita-Salute San Raffaele, Milan, Italy; 9Medical School, University of Exeter, Exeter, UK; 10Department of Nuclear Medicine, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK*These authors contributed equally to this workCorrespondence: Ivana RosenzweigSleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, Box 089, De Crespigny Park, London SE5 8AF, UKEmail ivana.1.rosenzweig@kcl.ac.ukIntroduction: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is increasingly recognised as an important precursor disease state of alpha-synucleinopathies. This parasomnia is characterized by a history of recurrent nocturnal dream enactment behaviour, loss of skeletal muscle atonia, and increased phasic muscle activity during REM sleep. Neuroimaging studies of striatal dopamine transporter uptake tracer signaling suggest increasing dopaminergic deficit across the continuum of the alpha-synucleinopathies, with early sleep dysfunction suggestive of early caudate dysfunction. Henceforth, we set out to investigate the relationship between early sleep changes and the striatal dopaminergic availability in iRBD.Methods: Twelve patients with iRBD, who had undergone a video polysomnography and a neuroimaging assessment of striatal dopamine transporter (DaT) uptake tracer signaling, and 22 matched controls who had similarly undergone a video polysomnography were retrospectively identified. Data were statistically analyzed to identify altered sleep parameters and correlate them with striatal dopamine transporter uptake tracer signaling.Results: The iRBD patients exhibited an increased number of periodic limb movements during sleep (P=0.001), compared to 22 age-matched healthy subjects. In addition, several significant links were found between regional DaT-uptakes and sleep architecture. Correlational analyses suggested a strong positive association between sleep fragmentation and dopamine deficiency in left caudate (r=− 0.630, P=0.028), whilst an increased uptake in the whole striatum was strongly linked to the sleep efficiency, and to a lesser degree to the length of sleep duration.Discussion: To the best of our knowledge, this is the first demonstration of a close relationship between dopaminergic availability in striatum and the quality of sleep in iRBD. Taken together, our exploratory findings suggest that subtle but functionally significant striatal changes in early stages of iRBD may contribute to the further shaping of sleep architecture.Keywords: isolated rapid eye movement behaviour disorder, polysomnography, sleep architecture, striatum, striatal dopamine transporter uptake tracer signalling imaging, DaTSCAN

Published
2021

2. Intraperitoneal delivery of acetate-encapsulated liposomal nanoparticles for neuroprotection of the penumbra in a rat model of ischemic stroke

Author

So PW, Ekonomou A, Galley K, Brody L, Sahuri-Arisoylu M, Rattray I, Cash D, and Bell JD

Subjects
ischemic stroke, acetate, liposomes, neuroinflammation, microglia, mid-cerebral artery occlusion, Medicine (General), R5-920
Abstract

Po-Wah So,1 Antigoni Ekonomou,1 Kim Galley,1 Leigh Brody,2 Meliz Sahuri-Arisoylu,2 Ivan Rattray,3 Diana Cash,1 Jimmy D Bell2 1King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Neuroimaging, London, UK; 2University of Westminster, Research Centre for Optimal Health, London, UK; 3King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Basic and Clinical Neuroscience, London, UK Background: Ischemic stroke is a devastating condition, with metabolic derangement and persistent inflammation enhancing the initial insult of ischaemia. Recombinant tissue plasminogen remains the only effective treatment but limited as therapy must commence soon after the onset of symptoms.Purpose: We investigated whether acetate, which modulates many pathways including inflammation, may attenuate brain injury in stroke. As acetate has a short blood half-life and high amounts irritate the gastrointestinal tract, acetate was administered encapsulated in a liposomal nanoparticle (liposomal-encapsulated acetate, LITA).Methods: Transient ischemia was induced by 90 mins middle-cerebral artery occlusion (MCAO) in Sprague-Dawley rats, and LITA or control liposomes given intraperitoneally at occlusion and daily for up to two weeks post-MCAO. Magnetic resonance imaging (MRI) was used to estimate lesion volume at 24 h, 1 and 2 weeks post-MCAO and anterior lateral ventricular volume (ALVv) at 2 weeks post-MCAO. Locomotive behaviour was tested prior to the final MRI scan. After the final scan, brains were collected, and immunohistochemistry was performed. Results: Lesion volumes were decreased by ~80% from 24 h to one-week post-MCAO, in both control and LITA groups (P

Published
2019

3. Longitudinal cerebral perfusion in presymptomatic genetic frontotemporal dementia: GENFI results

Author

Pasternak, M., Mirza, S., Luciw, N., Mutsaerts, H., (0000-0002-3201-6002) Petr, J., Thomas, D., Cash, D., Bocchetta, M., Tartaglia, C., Mitchell, S., Black, S., Freedman, M., Tang-Wai, D., Rogaeva, E., Russell, L., Bouzigues, A., Swieten, J., Jiskoot, L., Seelaar, H., Laforce Jr., R., Tiraboschi, P., Borroni, B., Galimberti, D., Rowe, J., Graff, C., Finger, E., Sandro, S., Mendonça, A., Butler, C., Gerhard, A., Sánchez-Valle, R., Moreno, F., Synofzik, M., Vandenberghe, R., Ducharme, S., Levin, J., Otto, M., Santana, I., Strafella, A., Macintosh, B., Rohrer, J., Masellis, M., Pasternak, M., Mirza, S., Luciw, N., Mutsaerts, H., (0000-0002-3201-6002) Petr, J., Thomas, D., Cash, D., Bocchetta, M., Tartaglia, C., Mitchell, S., Black, S., Freedman, M., Tang-Wai, D., Rogaeva, E., Russell, L., Bouzigues, A., Swieten, J., Jiskoot, L., Seelaar, H., Laforce Jr., R., Tiraboschi, P., Borroni, B., Galimberti, D., Rowe, J., Graff, C., Finger, E., Sandro, S., Mendonça, A., Butler, C., Gerhard, A., Sánchez-Valle, R., Moreno, F., Synofzik, M., Vandenberghe, R., Ducharme, S., Levin, J., Otto, M., Santana, I., Strafella, A., Macintosh, B., Rohrer, J., and Masellis, M.

Abstract

Genetic frontotemporal dementia is most commonly attributable to mutations in the C9orf72, GRN, or MAPT genes. The disease has near-complete penetrance, making presymptomatic carriers an ideal population for ascertaining the earliest changes in disease progression and the identification of suitable biomarkers for designing therapeutic trials when minimal neuronal loss has occurred. Cerebral perfusion, as measured by arterial spin labelling (ASL) MRI, has shown promise in being one such biomarker. However, longitudinal profiles of change in perfusion over time in presymptomatic carriers across all three genetic subgroups are lacking. Using data from the multicenter GENetic Frontotemporal dementia Initiative, we investigated longitudinal profiles of cerebral perfusion using ASL-MRI in C9orf72 (n = 42), GRN (n = 70), and MAPT (n = 31) presymptomatic mutation carriers and non-carrier controls (n = 158). ASL and T1w scans were processed with the ExploreASL pipeline to produce partial volume corrected perfusion images, which were parcellated to extract mean perfusion values from whole brain grey matter and regions defined by the second version of the automated anatomical atlas (AAL2). Linear mixed effects models were used to assess longitudinal perfusion change. Mutation carrier groups and non-carriers were statistically indistinguishable by baseline demographic and clinical measures. Decline in whole brain grey matter perfusion over time was more pronounced in all three carrier subgroups relative to controls, with changes most pronounced in GRN, followed by C9orf72 and MAPT variants. Additionally, GRN and MAPT groups featured global grey matter hypoperfusion relative to non-carrier controls as early as one year after baseline measurement, with C9orf72 featuring significant hypoperfusion after two years. Region of interest analysis demonstrated that each genetic subgroup had its own regional profile in terms of longitudinal perfusion decline. Perfusion decline in C9orf72

Published
2024

4. Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia

Author

Bussy, A., Levy, J., Best, T., Patel, R., Cupo, L., Van Langenhove, T., Nielsen, J., Pijnenburg, Y., Waldö, M., Remes, A., Schroeter, M., Santana, I., Pasquier, F., Otto, M., Danek, A., Levin, J., Le Ber, I., Vandenberghe, R., Synofzik, M., Moreno, F., de Mendonça, A., Sanchez‐Valle, R., Laforce, R., Langheinrich, T., Gerhard, A., Graff, C., Butler, C., Sorbi, S., Jiskoot, L., Seelaar, H., van Swieten, J., Finger, E., Tartaglia, M., Masellis, M., Tiraboschi, P., Galimberti, D., Borroni, B., Rowe, J., Bocchetta, M., Rohrer, J., Devenyi, G., Chakravarty, M., Ducharme, S., Esteve, A., Nelson, A., Bouzigues, A., Heller, C., Greaves, C., Cash, D., Thomas, D., Todd, E., Benotmane, H., Zetterberg, H., Swift, I., Nicholas, J., Samra, K., Russell, L., Shafei, R., Convery, R., Timberlake, C., Cope, T., Rittman, T., Benussi, A., Premi, E., Gasparotti, R., Archetti, S., Gazzina, S., Cantoni, V., Arighi, A., Fenoglio, C., Scarpini, E., Fumagalli, G., Borracci, V., Rossi, G., Giaccone, G., Di Fede, G., Caroppo, P., Prioni, S., Redaelli, V., Tang‐Wai, D., Rogaeva, E., Castelo‐Branco, M., Freedman, M., Keren, R., Black, S., Mitchell, S., Shoesmith, C., Bartha, R., Rademakers, R., Poos, J., Papma, J., Giannini, L., van Minkelen, R., Nacmias, B., Ferrari, C., Polito, C., Lombardi, G., Bessi, V., Veldsman, M., Andersson, C., Thonberg, H., Öijerstedt, L., Jelic, V., Thompson, P., Lladó, A., Antonell, A., Olives, J., Balasa, M., Bargalló, N., Borrego‐Ecija, S., Verdelho, A., Maruta, C., Ferreira, C., Miltenberger, G., do Couto, F., Gabilondo, A., Gorostidi, A., Villanua, J., Cañada, M., Tainta, M., Zulaica, M., Barandiaran, M., Alves, P., Bender, B., Wilke, C., Graf, L., Vogels, A., Vandenbulcke, M., Van Damme, P., Bruffaerts, R., Poesen, K., Rosa‐Neto, P., Gauthier, S., Camuzat, A., Brice, A., Bertrand, A., Funkiewiez, A., Rinaldi, D., Saracino, D., Colliot, O., Sayah, S., Prix, C., Wlasich, E., Wagemann, O., Loosli, S., Schönecker, S., Hoegen, T., Lombardi, J., Anderl‐Straub, S., Rollin, A., Kuchcinski, G., Bertoux, M., Lebouvier, T., Deramecourt, V., Santiago, B., Duro, D., Leitão, M., Almeida, M., Tábuas‐Pereira, M., Afonso, S., Engel, A., Polyakova, M., Erasmus MC other, Neurology, Radiology & Nuclear Medicine, Clinical Genetics, GENetic Frontotemporal dementia Initiative (GENFI), Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Engel, Annerose, Polyakova, Maryna, Esteve, Aitana Sogorb, Nelson, Annabel, Bouzigues, Arabella, Heller, Carolin, Greaves, Caroline V, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Nicholas, Jennifer, Samra, Kiran, Russell, Lucy L, Bocchetta, Martina, Shafei, Rachelle, Convery, Rhian S, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Bussy, Aurélie [0000-0001-6695-9941], Nielsen, Jørgen E [0000-0003-0453-5582], Borroni, Barbara [0000-0001-9340-9814], Bocchetta, Martina [0000-0003-1814-5024], Devenyi, Gabriel A [0000-0002-7766-1187], Apollo - University of Cambridge Repository, and Amsterdam Neuroscience - Neurodegeneration

Subjects
C9orf72 Protein, Radiological and Ultrasound Technology, Medizin, frontotemporal dementia, Neurology, Frontotemporal Dementia, Cerebellum, Humans, magnetic resonance imaging, genetics, neuropsychiatry, Radiology, Nuclear Medicine and imaging, Human medicine, ddc:610, Neurology (clinical), Atrophy, Anatomy, genetics [Frontotemporal Dementia], genetics [C9orf72 Protein]
Abstract

Funder: Alzheimer Society of Canada; Id: http://dx.doi.org/10.13039/501100000143, Funder: Weston Brain Institute; Id: http://dx.doi.org/10.13039/100012479, Funder: Fonds de Recherche du Québec ‐ Santé, Funder: Canadian Institutes of Health Research; Id: http://dx.doi.org/10.13039/501100000024, Funder: NIHR Rare Diseases Translational Research Collaboration, Funder: Deutsche Forschungsgemeinschaft; Id: http://dx.doi.org/10.13039/501100001659, Recent studies have reported early cerebellar and subcortical impact in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the cerebello-subcortical circuitry in FTD has been understudied despite its essential role in cognition and behaviors related to FTD symptomatology. The present study aims to investigate the association between cerebellar and subcortical atrophy, and neuropsychiatric symptoms across genetic mutations. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative including mutation carriers and noncarrier first-degree relatives of known symptomatic carriers. Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed, and partial least squares analyses (PLS) were used to link morphometry and behavior. In presymptomatic C9orf72 expansion carriers, thalamic atrophy was found compared to noncarriers, suggesting the importance of this structure in FTD prodromes. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to neuropsychiatric symptoms, with significant overlap in brain/behavior patterns, but also specificity for each genetic mutation group. The largest differences were in the cerebellar atrophy (larger extent in C9orf72 expansion group) and more prominent amygdalar volume reduction in the MAPT group. Brain scores in the C9orf72 expansion carriers and MAPT carriers demonstrated covariation patterns concordant with atrophy patterns detectable up to 20 years before expected symptom onset. Overall, these results demonstrated the important role of the subcortical structures in genetic FTD symptom expression, particularly the cerebellum in C9orf72 and the amygdala in MAPT carriers.

Published
2023
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6. Motor symptoms in genetic frontotemporal dementia: developing a new module for clinical rating scales

Author

Samra, K, MacDougall, AM, Peakman, G, Bouzigues, A, Bocchetta, M, Cash, DM, Greaves, CV, Convery, RS, van Swieten, JC, Jiskoot, L, Seelaar, H, Butler, CR, Fenoglio, C, Rohrer, JD, Gerhard, A, Ducharme, S, Le Ber, I, Tiraboschi, P, Santana, I, Pasquier, F, Levin, J, Shoesmith, C, Otto, M, Russell, LL, Nelson, A, Cash, D, Thomas, DL, Todd, E, Ferrari, C, Benotmane, H, Timberlake, C, Gabilondo, A, Cope, T, Rittman, T, Benussi, A, Premi, E, Gasparotti, R, Thompson, P, Archetti, S, Fumagalli, G, do Couto, FS, Borracci, V, Polito, C, Rossi, G, Giaccone, G, Di Fede, G, Caroppo, P, Ferreira, CB, Prioni, S, Langheinrich, T, Redaelli, V, Lladó, A, Bartha, R, Tang-Wai, D, Rogaeva, E, Castelo-Branco, M, Freedman, M, Keren, R, Black, S, Mitchell, S, Miltenberger, G, Rademakers, R, Poos, J, Papma, JM, Giannini, L, van Minkelen, R, Pijnenburg, Y, Gauthier, S, Nacmias, B, Lombardi, G, Bessi, V, Veldsman, M, Andersson, C, Thonberg, H, Öijerstedt, L, Prix, C, Jelic, V, Antonell, A, Graff, C, Olives, J, Balasa, M, Bargalló, N, Borrego-Ecija, S, Verdelho, A, Kuchcinski, G, Maruta, C, Gorostidi, A, Laforce, R, Villanua, J, Wlasich, E, Cañada, M, Tainta, M, Zulaica, M, Barandiaran, M, Moreno, F, Alves, P, Bender, B, Bertoux, M, Wilke, C, Lebouvier, T, Camuzat, A, Graf, L, Vogels, A, Vandenbulcke, M, Van Damme, P, Bruffaerts, R, Poesen, K, Rosa-Neto, P, Sanchez-Valle, R, Brice, A, Bertrand, A, Funkiewiez, A, Rinaldi, D, Saracino, D, Colliot, O, Sorbi, S, Sayah, S, Wagemann, O, Loosli, S, Schönecker, S, Hoegen, T, Lombardi, J, Anderl-Straub, S, Nicholas, J, Rollin, A, Deramecourt, V, Arighi, A, Santiago, B, Duro, D, Leitão, MJ, Almeida, MR, Tábuas-Pereira, M, Gazzina, S, Afonso, S, Masellis, M, Tartaglia, C, Shafei, R, Rowe, JB, Borroni, B, Finger, E, Synofzik, M, Galimberti, D, Vandenberghe, R, de Mendonça, A, Cantoni, V, Genetic FTD Initiative (GENFI), Samra, Kiran [0000-0002-3105-7099], Apollo - University of Cambridge Repository, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Nelson, Annabel, Bocchetta, Martina, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, and Verdelho, Ana

Subjects
Progranulin, Clinical Neurology, C9ORF72, tau Proteins, AMYOTROPHIC-LATERAL-SCLEROSIS, diagnosis [Frontotemporal Dementia], C9orf72, Tremor, Genetics, Humans, ddc:610, genetics [Frontotemporal Dementia], genetics [C9orf72 Protein], MUTATION, Science & Technology, C9orf72 Protein, HERITABILITY, Amyotrophic Lateral Sclerosis, PROGRESSIVE SUPRANUCLEAR PALSY, COGNITIVE IMPAIRMENT, REPEAT EXPANSION, genetics [tau Proteins], Motor, PATHOLOGICAL FEATURES, Neurology, FOS: Biological sciences, Frontotemporal Dementia, Mutation, Human medicine, Neurosciences & Neurology, Neurology (clinical), Tau, TAU, Life Sciences & Biomedicine, Frontotemporal dementia, PARKINSONISM
Abstract

Funder: CIBERNED, Funder: Canadian Institutes of Health Research; doi: http://dx.doi.org/10.13039/501100000024, Funder: Lemaire Family Foundation, Funder: Swedish Frontotemporal Dementia Initiative, Funder: Italian Ministry of Health, Funder: Weston Brain Institute; doi: http://dx.doi.org/10.13039/100012479, Funder: Mady Browaaeys Fund, Funder: Miriam Marks Brain Research UK, Funder: Bluefield Project, OBJECTIVE: To investigate the optimal method of adding motor features to a clinical rating scale for frontotemporal dementia (FTD). METHODS: Eight hundred and thirty-two participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 522 mutation carriers (with C9orf72, GRN and MAPT mutations) and 310 mutation-negative controls. A standardised clinical questionnaire was used to assess eight motor symptoms (dysarthria, dysphagia, tremor, slowness, weakness, gait disorder, falls and functional difficulties using hands). Frequency and severity of each motor symptom was assessed, and a principal component analysis (PCA) was performed to identify how the different motor symptoms loaded together. Finally, addition of a motor component to the CDR® plus NACC FTLD was investigated (CDR® plus NACC FTLD-M). RESULTS: 24.3% of mutation carriers had motor symptoms (31.7% C9orf72, 18.8% GRN, 19.3% MAPT) compared to 6.8% of controls. Slowness and gait disorder were the commonest in all genetic groups while tremor and falls were the least frequent. Symptom severity scores were similar to equivalent physical motor examination scores. PCA revealed that all motor symptoms loaded together so a single additional motor component was added to the CDR® plus NACC FTLD to form the CDR® plus NACC FTLD-M. Individual global scores were more severe with the CDR® plus NACC FTLD-M, and no patients with a clinically diagnosed motor disorder (ALS/FTD-ALS or parkinsonism) were classified anymore as asymptomatic (unlike the CDR® plus NACC FTLD alone). CONCLUSIONS: Motor features are present in mutation carriers at all disease stages across all three genetic groups. Inclusion of motor symptoms in a rating scale that can be used in future clinical trials will not only ensure a more accurate severity measure is recorded but that a wider spectrum of FTD phenotypes can be included in the same trial.

Published
2022
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7. A consensus protocol for functional connectivity analysis in the rat brain

Author

Grandjean, J., Desrosiers-Gregoire, G., Anckaerts, C., Angeles-Valdez, D., Ayad, F., Barrière, D., Blockx, I., Bortel, A., Broadwater, M., Cardoso, B., Célestine, M., Chavez-Negrete, J., Choi, S., Christiaen, E., Clavijo, P., Colon-Perez, L., Cramer, S., Daniele, T., Dempsey, E., Diao, Y., Doelemeyer, A., Dopfel, D., Dvořáková, L., Falfán-Melgoza, C., Fernandes, F., Fowler, C., Fuentes-Ibañez, A., Garin, C., Gelderman, E., Golden, C., Guo, C., Henckens, M., Hennessy, L., Herman , P., Hofwijks, N., Horien, C., Ionescu, T., Jones, J., Kaesser, J., Kim, E., Lambers, H., Lazari, A., Lee, S., Lillywhite, A., Liu, Y., López-Castro, A., López-Gil , X., Ma, Z., MacNicol, E., Madularu, D., Mandino, F., Marciano, S., McAuslan, M., McCunn, P., McIntosh, A., Meng, X., Meyer-Baese, L., Missault, S., Moro, F., Naessens, D., Nava-Gomez, L., Nonaka, H., Ortiz, J., Paasonen, J., Pais-Roldán, P., Peeters, L., Pereira, M., Perez, P., Pompilus, M., Prior, M., Rakhmatullin, R., Reimann, H., Reinwald, J., Triana Del Rio, R., Rivera-Olvera, A., Ruiz-Pérez, D., Russo, G., Rutten, T., Ryoke, R., Sack, M., Salvan, P., Sanganahalli, B., Schroeter, A., Seewoo , B., Selingue, E., Seuwen, A., Shi, B., Sirmpilatze, N., Smith, J., Smith, C., Sobczak, F., Stenroos, P., Straathof, M., Strobelt, S., Sumiyoshi, A., Takahashi, K., Torres-García, M., Tudela, R., van den Berg, M., van der Marel, K., van Hout, A., Vertullo, R., Vidal, B., Vrooman, R., Wang, X., Wank, I., Watson, D., Yin, T., Zhang, Y., Zurbruegg, S., Achard, S., Alcauter, S., Auer, D., Barbier, E., Baudewig, J., Beckmann, C., Beckmann, N., Becq, G., Blezer, E., Bolbos, R., Boretius, S., Bouvard, S., Budinger, E., Buxbaum, J., Cash, D., Chapman, V., Chuang, K., Ciobanu, L., Coolen, B., Dalley, J., Dhenain, M., Dijkhuizen, R., Esteban, O., Faber, C., Febo, M., Feindel, K., Forloni, G., Fouquet, J., Garza-Villarreal, E., Gass, N., Glennon, J., Gozzi, A., Gröhn, O., Harkin, A., Heerschap, A., Helluy, X., Herfert , K., Heuser, A., Homberg, J., Houwing, D., Hyder, F., Ielacqua, G., Jelescu, I., Johansen-Berg, H., Kaneko, G., Kawashima, R., Keilholz, S., Keliris, G., Kelly, C., Kerskens, C., Khokhar, J., Kind, P., Langlois, J., Lerch, J., López-Hidalgo, M., Manahan-Vaughan, D., Marchand, F., Mars, R., Marsella, G., Micotti , E., Muñoz-Moreno , E., Near, J., Niendorf, T., Otte, W., Pan , W., Prado-Alcalá, R., Quirarte, G., Rodger , J., Rosenow, T., Sampaio-Baptista, C., Sartorius, A., Sawiak, S., Scheenen, T., Shemesh, Shih, Y., Shmuel, A., Soria, G., Stoop, R., Thompson, G., Till, S., Todd, N., Van Der Linden, A., van der Toorn, A., van Tilborg, G., Vanhove, C., Veltien, A., Verhoye, M., Wachsmuth, L., Weber-Fahr, W., Wenk , P., Yu, X., Zerbi , V., Zhang , N., Zhang, B., Zimmer, L., Devenyi, G., Chakravarty, M., and Hess, A.

Subjects
Action, intention, and motor control, General Neuroscience, fmri, Medizin, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Human medicine
Abstract

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for comparisons with data modalities collected under invasive or terminal procedures. Currently, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. Here we introduce StandardRat, a consensus rat functional magnetic resonance imaging acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired from rats across 46 centers. We developed a reproducible pipeline for analyzing rat data acquired with diverse protocols and determined experimental and processing parameters associated with the robust detection of functional connectivity across centers. We show that the standardized protocol enhances biologically plausible functional connectivity patterns relative to previous acquisitions. The protocol and processing pipeline described here is openly shared with the neuroimaging community to promote interoperability and cooperation toward tackling the most important challenges in neuroscience. The authors pooled resources to identify best practices and develop a new standardized protocol for estimating functional connectivity in rats with magnetic resonance imaging.

Published
2023
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8. Associations between ASL-derived cerebrovascular health and cognitive performance: results from the Insight 46 study

Author

Dijsselhof, M. B., Lu, K., Lorenzini, L., Collij, L. E., James, S.-N., Thomas, D. L., Scott, C. J., Manning, E. N., Cash, D. M., Hughes, A. D., Richard, M., Barkhof, F., Schott, J. M., (0000-0002-3201-6002) Petr, J., Mutsaerts, H. J. M. M., Dijsselhof, M. B., Lu, K., Lorenzini, L., Collij, L. E., James, S.-N., Thomas, D. L., Scott, C. J., Manning, E. N., Cash, D. M., Hughes, A. D., Richard, M., Barkhof, F., Schott, J. M., (0000-0002-3201-6002) Petr, J., and Mutsaerts, H. J. M. M.

Abstract

Cardiovascular and cerebrovascular pathology may accelerate brain aging and cognitive decline. Structural cerebrovascular imaging biomarkers, such as white matter hyperintensities, reflect mostly irreversible accumulated damage. In contrast, cerebral blood flow (CBF), measured with arterial spin labelling (ASL) perfusion MRI, is a potential early haemodynamic biomarker of cognitive impairment. However, our understanding of physiological CBF variability and its relation with cognition is limited.

Published
2023

9. Cardiovascular and cerebrovascular health in 70-year-olds: a population-based ASL study

Author

Dijsselhof, M. B. J., James, S.-N., Lorenzini, L., Collij, L., Thomas, D. L., Scott, C., Manning, E., Józsa, T. I., Cash, D., Study, I., Sudre, C., Hughes, A. D., Richards, M., Barkhof, F., Schott, J., (0000-0002-3201-6002) Petr, J., Mutsaerts, H. J. M. M., Dijsselhof, M. B. J., James, S.-N., Lorenzini, L., Collij, L., Thomas, D. L., Scott, C., Manning, E., Józsa, T. I., Cash, D., Study, I., Sudre, C., Hughes, A. D., Richards, M., Barkhof, F., Schott, J., (0000-0002-3201-6002) Petr, J., and Mutsaerts, H. J. M. M.

Abstract

While mid-life cardiovascular pathology may lead to late-life cognitive decline, our understanding of the role of cerebrovascular health as an intermediate biomarker is limited. We explored the association between cardiovascular health biomarkers and cross-sectional and longitudinal cerebrovascular health assessed by ASL MRI in Insight46, a well-characterised cognitively normal population-based sample. We found several cross-sectional and longitudinal associations between blood pressure and CBF. These findings suggest that the effects of BP on cerebrovascular health can be imaged with ASL perfusion MRI, possibly offering opportunities to prevent or intervene before cognitive decline sets in.

Published
2023

10. Author Correction: A consensus protocol for functional connectivity analysis in the rat brain

Author

Grandjean, J., Desrosiers-Gregoire, G., Anckaerts, C., Angeles-Valdez, D., Ayad, F., Barrière, D., Blockx, I., Bortel, A., Broadwater, M., Cardoso, B., Célestine, M., Chavez-Negrete, J., Choi, S., https://orcid.org/0000-0001-7327-1344, Christiaen, E., Clavijo, P., Colon-Perez, L., Cramer, S., Daniele, T., Dempsey, E., Diao, Y., Doelemeyer, A., Dopfel, D., Dvořáková, L., Falfán-Melgoza, C., Fernandes, F., Fowler, C., Fuentes-Ibañez, A., Garin, C., Gelderman, E., Golden, C., Guo, C., Henckens, M., Hennessy, L., Herman , P., Hofwijks, N., Horien, C., Ionescu, T., Jones, J., Kaesser, J., Kim, E., Lambers, H., Lazari, A., Lee, S., Lillywhite, A., Liu, Y., López-Castro, A., López-Gil , X., Ma, Z., MacNicol, E., Madularu, D., Mandino, F., Marciano, S., McAuslan, M., McCunn, P., McIntosh, A., Meng, X., Meyer-Baese, L., Missault, S., Moro, F., Naessens, D., Nava-Gomez, L., Nonaka, H., Ortiz, J., Paasonen, J., Pais-Roldán, P., https://orcid.org/0000-0002-9381-3048, Peeters, L., Pereira, M., Perez, P., Pompilus, M., Prior, M., Rakhmatullin, R., Reimann, H., Reinwald, J., Triana Del Rio, R., Rivera-Olvera, A., Ruiz-Pérez, D., Russo, G., Rutten, T., Ryoke, R., Sack, M., Salvan, P., Sanganahalli, B., Schroeter, A., Seewoo , B., Selingue, E., Seuwen, A., Shi, B., Sirmpilatze, N., Smith, J., Smith, C., Sobczak, F., Stenroos, P., Straathof, M., Strobelt, S., Sumiyoshi, A., Takahashi, K., Torres-García, M., Tudela, R., van den Berg, M., van der Marel, K., van Hout, A., Vertullo, R., Vidal, B., Vrooman, R., Wang, X., Wank, I., Watson, D., Yin, T., Zhang, Y., Zurbruegg, S., Achard, S., Alcauter, S., Auer, D., Barbier, E., Baudewig, J., Beckmann, C., Beckmann, N., Becq, G., Blezer, E., Bolbos, R., Boretius, S., Bouvard, S., Budinger, E., Buxbaum, J., Cash, D., Chapman, V., Chuang, K., Ciobanu, L., Coolen, B., Dalley, J., Dhenain, M., Dijkhuizen, R., Esteban, O., Faber, C., Febo, M., Feindel, K., Forloni, G., Fouquet, J., Garza-Villarreal, E., Gass, N., Glennon, J., Gozzi, A., Gröhn, O., Harkin, A., Heerschap, A., Helluy, X., Herfert , K., Heuser, A., Homberg, J., Houwing, D., Hyder, F., Ielacqua, G., Jelescu, I., Johansen-Berg, H., Kaneko, G., Kawashima, R., Keilholz, S., Keliris, G., Kelly, C., Kerskens, C., Khokhar, J., Kind, P., Langlois, J., Lerch, J., López-Hidalgo, M., Manahan-Vaughan, D., Marchand, F., Mars, R., Marsella, G., Micotti , E., Muñoz-Moreno , E., Near, J., Niendorf, T., Otte, W., Pan , W., Prado-Alcalá, R., Quirarte, G., Rodger , J., Rosenow, T., Sampaio-Baptista, C., Sartorius, A., Sawiak, S., Scheenen, T., Shemesh, Shih, Y., Shmuel, A., https://orcid.org/0000-0003-3028-6639, Soria, G., Stoop, R., https://orcid.org/0000-0002-3532-1512, Thompson, G., Till, S., Todd, N., Van Der Linden, A., van der Toorn, A., van Tilborg, G., Vanhove, C., Veltien, A., Verhoye, M., Wachsmuth, L., Weber-Fahr, W., Wenk , P., Yu, X., Zerbi , V., Zhang , N., Zhang, B., Zimmer, L., Devenyi, G., Chakravarty, M., and Hess, A.

Subjects
General Neuroscience, Medizin
Abstract

Weitere Nicht-UDE Autoren sind nicht mit aufgeführt. in press

Published
2023
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13. Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia

Author

Panman, J. L., Venkatraghavan, V., Van Der Ende, E. L., Steketee, R. M. E., Jiskoot, L. C., Poos, J. M., Dopper, E. G. P., Meeter, L. H. H., Kaat, L. D., Rombouts, S. A. R. B., Vernooij, M. W., Kievit, A. J. A., Premi, E., Cosseddu, M., Bonomi, E., Olives, J., Rohrer, J. D., Sanchez-Valle, R., Borroni, B., Bron, E. E., Van Swieten, J. C., Papma, J. M., Klein, S., Afonso, S., Almeida, M. R., Anderl-Straub, S., Andersson, C., Antonell, A., Archetti, S., Arighi, A., Balasa, M., Barandiaran, M., Bargallo, N., Bartha, R., Bender, B., Black, S., Butler, C., Bocchetta, M., Borrego-Ecija, S., Bras, J., Bruffaerts, R., Caroppo, P., Cash, D., Castelo-Branco, M., Convery, R., Cope, T., Danek, A., De Arriba, M., De Mendonca, A., Di Fede, G., Diaz, Z., Ducharme, S., Duro, D., Fenoglio, C., Ferreira, C. B., Finger, E., Flanagan, T., Fox, N., Freedman, M., Fumagalli, G., Gabilondo, A., Galimberti, D., Gasparotti, R., Gauthier, S., Gazzina, S., Gerhard, A., Giaccone, G., Gorostidi, A., Graff, C., Greaves, C., Guerreiro, R., Heller, C., Hoegen, T., Indakoetxea, B., Jelic, V., Karnath, H. -O., Keren, R., Laforce, R., Leitao, M. J., Levin, J., Llado, A., Loosli, S., Maruta, C., Masellis, M., Mead, S., Miltenberger, G., Van Minkelenm Sara Mitchell, R., Moore, K., Moreno, F., Nicholas, J., Oijerstedt, L., Otto, M., Ourselin, S., Padovani, A., Peakman, G., Pijnenburg, Y., Polito, C., Prioni, S., Prix, C., Rademakers, R., Redaelli, V., Rittman, T., Rogaeva, E., Rosa-Neto, P., Rossi, G., Rosser, M., Rowe, J., Santana, I., Santiago, B., Scarpini, E., Schonecker, S., Shafei, E. S. R., Shoesmith, C., Synofzik, M., Tabuas-Pereira, M., Tagliavini, F., Tartaglia, C., Tainta, M., Taipa, R., Tang-Wai, D., Thomas, D. L., Thonberg, H., Timberlake, C., Tiraboschi, P., Todd, E., Vandamme, P., Vandenberghe, R., Vandenbulcke, M., Veldsman, M., Verdelho, A., Villanua, J., Warren, J., Wilkeione, C., Elisabeth, W., Henrik, W., Zulaica, Z. M., Neurology, Physics and medical technology, Radiology & Nuclear Medicine, Clinical Genetics, and Medical Research Council

Subjects
Male, Oncology, Disease, Neuropsychological Tests, GENFI consortium investigators, Primary progressive aphasia, Cognition, Progranulins, 0302 clinical medicine, Neurofilament Proteins, BEHAVIORAL VARIANT, HETEROGENEITY, Gray Matter, 11 Medical and Health Sciences, Language, Psychiatry, 0303 health sciences, Brain, Middle Aged, Magnetic Resonance Imaging, White Matter, 17 Psychology and Cognitive Sciences, ALZHEIMERS-DISEASE, Psychiatry and Mental health, Phenotype, medicine.anatomical_structure, Frontotemporal Dementia, Disease Progression, Biomarker (medicine), Female, Life Sciences & Biomedicine, Frontotemporal dementia, medicine.medical_specialty, Clinical Neurology, EVENT-BASED MODEL, Grey matter, Lateralization of brain function, White matter, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, NEUROFILAMENT LIGHT-CHAIN, medicine, Humans, LOBAR DEGENERATION, PROGRANULIN, Aged, 030304 developmental biology, Science & Technology, Neurology & Neurosurgery, business.industry, DISEASE PROGRESSION, medicine.disease, Mutation, WHITE-MATTER INTEGRITY, Surgery, Neurosciences & Neurology, Neurology (clinical), business, GENFI, Biomarkers, 030217 neurology & neurosurgery, Progressive disease
Abstract

ObjectiveProgranulin-related frontotemporal dementia (FTD-GRN) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation carriers. In this cross-sectional study, we estimated the temporal cascade of biomarker changes for FTD-GRN, in a data-driven way.MethodsWe included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non-carriers. Selected biomarkers were neurofilament light chain (NfL), grey matter volume, white matter microstructure and cognitive domains. We used discriminative event-based modelling to infer the cascade of biomarker changes in FTD-GRN and estimated individual disease severity through cross-validation. We derived the biomarker cascades in non-fluent variant primary progressive aphasia (nfvPPA) and behavioural variant FTD (bvFTD) to understand the differences between these phenotypes.ResultsLanguage functioning and NfL were the earliest abnormal biomarkers in FTD-GRN. White matter tracts were affected before grey matter volume, and the left hemisphere degenerated before the right. Based on individual disease severities, presymptomatic carriers could be delineated from symptomatic carriers with a sensitivity of 100% and specificity of 96.1%. The estimated disease severity strongly correlated with functional severity in nfvPPA, but not in bvFTD. In addition, the biomarker cascade in bvFTD showed more uncertainty than nfvPPA.ConclusionDegeneration of axons and language deficits are indicated to be the earliest biomarkers in FTD-GRN, with bvFTD being more heterogeneous in disease progression than nfvPPA. Our data-driven model could help identify presymptomatic GRN mutation carriers at risk of conversion to the clinical stage.

Published
2021
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15. Multimodal MRI-derived phenotypes in preclinical Alzheimer’s Disease: results from the EPAD cohort

Author

Lorenzini, L., Ingala, S., Wink, A. M., Kuijer, J. P. A., Wottschel, V., Sudre, C. H., Haller, S., Molinuevo, J. L., Gispert, J. D., Cash, D. M., Thomas, D. L., Vos, S. B., Ferran, P., (0000-0002-3201-6002) Petr, J., Wolz, R., Palombit, A., Schwarz, A. J., Chételat, G., Payoux, P., Di Perri, C., Pernet, C., Frisoni, G., Fox, N. C., Ritchie, C., Wardlaw, J., Waldman, A., Barkhof, F., Mutsaerts, H. J. M. M., Lorenzini, L., Ingala, S., Wink, A. M., Kuijer, J. P. A., Wottschel, V., Sudre, C. H., Haller, S., Molinuevo, J. L., Gispert, J. D., Cash, D. M., Thomas, D. L., Vos, S. B., Ferran, P., (0000-0002-3201-6002) Petr, J., Wolz, R., Palombit, A., Schwarz, A. J., Chételat, G., Payoux, P., Di Perri, C., Pernet, C., Frisoni, G., Fox, N. C., Ritchie, C., Wardlaw, J., Waldman, A., Barkhof, F., and Mutsaerts, H. J. M. M.

Abstract

Image-derived phenotypes (IDPs) from multimodal MRI sequences constitute an important resource that allows the characterization of brain alterations in the early stages of Alzheimer diseases and other neurodegenerative conditions. Here, we showed the computation of multimodal IDPs from the European Prevention of Alzheimer Dementia (EPAD) cohort and assessed their relationship with non-imaging markers of neurodegeneration. We demonstrated the clinical relevance of IDPs to uncover early brain alteration in AD by showing expected association with non-imaging data.

Published
2022

16. The Open-Access European Prevention of Alzheimer’s Dementia (EPAD) MRI dataset and processing workflow

Author

Lorenzini, L., Ingala, S., Wink, A. M., Kuijer, J. P. A., Wottschel, V., Dijsselhof, M., Sudre, C. H., Haller, S., Molinuevo, J. L., Gispert, J. D., Cash, D. M., Thomas, D. L., Vos, S. B., Prados, F., (0000-0002-3201-6002) Petr, J., Wolz, R., Palombit, A., Schwarz, A. J., Chételat, G., Payoux, P., Di Perri, C., Wardlaw, J. M., Frisoni, G. B., Foley, C., Fox, N. C., Ritchie, C., Pernet, C., Waldman, A., Barkhof, F., Mutsaerts, H. J. M. M., Lorenzini, L., Ingala, S., Wink, A. M., Kuijer, J. P. A., Wottschel, V., Dijsselhof, M., Sudre, C. H., Haller, S., Molinuevo, J. L., Gispert, J. D., Cash, D. M., Thomas, D. L., Vos, S. B., Prados, F., (0000-0002-3201-6002) Petr, J., Wolz, R., Palombit, A., Schwarz, A. J., Chételat, G., Payoux, P., Di Perri, C., Wardlaw, J. M., Frisoni, G. B., Foley, C., Fox, N. C., Ritchie, C., Pernet, C., Waldman, A., Barkhof, F., and Mutsaerts, H. J. M. M.

Abstract

The European Prevention of Alzheimer Dementia (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of Alzheimer’s Disease. The EPAD imaging dataset includes core (3D T1w, 3D FLAIR) and advanced (ASL, diffusion MRI, and resting-state fMRI) MRI sequences. Here, we give an overview of the semi-automatic multimodal and multisite pipeline that we developed to curate, preprocess, quality control (QC), and compute image-derived phenotypes (IDPs) from the EPAD MRI dataset. This pipeline harmonizes DICOM data structure across sites and performs standardized MRI pre- processing steps. A semi-automated MRI QC procedure was implemented to visualize and flag MRI images next to site-specific distributions of QC features — i.e. metrics that represent image quality. The value of each of these QC features was evaluated through comparison with visual assessment and step-wise parameter selection based on logistic regression. IDPs were computed from 5 different MRI modalities and their sanity and potential clinical relevance were ascertained by assessing their relationship with biological markers of aging and dementia. The EPAD v1500.0 data release encompassed core structural scans from 1356 participants 842 fMRI, 831 dMRI, and 858 ASL scans. From 1356 3D T1w images, we identified 17 images with poor quality and 61 with moderate quality. Five QC features — Signal to Noise Ratio (SNR), Contrast to Noise Ratio (CNR), Coefficient of Joint Variation (CJV), Foreground-Background energy Ratio (FBER), and Image Quality Rate (IQR) — were selected as the most informative on image quality by comparison with visual assessment. The multimodal IDPs showed greater impairment in associations with age and dementia biomarkers, demonstrating the potential of the dataset for future clinical analyses.

Published
2022

18. Erbb4 deletion from fast-spiking interneurons causes psychosis-relevant neuroimaging phenotypes

Author

Kiemes, A., primary, Serrano Navacerrada, M. E., additional, Kim, E., additional, Randall, K., additional, Simmons, C., additional, Rojo Gonzalez, L., additional, Petrinovic, M.M., additional, Lythgoe, D.J., additional, Rotaru, D., additional, Di Censo, D., additional, Hirshler, L., additional, Barbier, E. L., additional, Vernon, A. C., additional, Stone, J. M., additional, Davies, C., additional, Cash, D., additional, and Modinos, G., additional

Published
2022
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21. Scrutiny of the Bounty or Teaching Critical Thinking in

Author

Cash, D. Michele

Abstract

This paper, presented at the Indiana Library Association Meeting, discusses critical thinking in general terms and then briefly discusses why it is important to include critical thinking skills in bibliographic instruction sessions at the higher education level. A discussion of the instructional design of bibliographic instruction in relation to teaching critical thinking is followed by specific examples of how one educator has incorporated critical thinking skills into library instruction sessions. A 19-item bibliography divided into sections on Critical Thinking in General and Critical Thinking in Library Instruction is included. (THC)

Published
1985

22. Neuroimaging Pre-Processing and Quality Control for The European Prevention of Alzheimer's Dementia (EPAD) Cohort Study

Author

Lorenzini, L., Ingala, S., Wink, A. M., Kuijer, J., Wottschel, V., Sudre, C., Haller, S., Molinuevo, J. L., Gispert, J. D., Cash, D., Thomas, D., Vos, S., Prados Carrasco, F., Petr, J., Wolz, R., Palombit, A., Schwarz, A., Chételat, G., Payoux, P., Di Perri, C., Pernet, C., Giovanni, F., Fox, N., Ritchie, C., Wardlaw, J., Waldman, A., Barkhof, F., and Mutsaerts, H.

Abstract

The neuroimaging community strives to obtain large data cohorts, usually through association within consortia spanning different sites and countries. This results in increased variability of acquisition parameters and scan quality, which can affect image processing and statistical analyses. We propose a semi-automatic data management pipeline to process raw data, assess quality and compute image-derived phenotypes from multi-modal MRI scans, as developed for the multi-centre European Prevention of Alzheimer Dementia longitudinal cohort study (EPAD LCS).

Published
2021

23. Periodic limb movements during sleep:A narrative review

Author

Drakatos, P, Olaithe, M, Verma, D, Ilic, K, Cash, D, Fatima, Y, Higgins, S, Young, A H, Chaudhuri, K R, Steier, J, Skinner, Timothy, Bucks, R, Rosenzweig, I, Drakatos, P, Olaithe, M, Verma, D, Ilic, K, Cash, D, Fatima, Y, Higgins, S, Young, A H, Chaudhuri, K R, Steier, J, Skinner, Timothy, Bucks, R, and Rosenzweig, I

Abstract

Objective: Using narrative review techniques, this paper evaluates the evidence for separable underlying patho-mechanisms of periodic limb movements (PLMs) to separable PLM motor patterns and phenotypes, in order to elucidate potential new treatment modalities. Background: Periodic limb movement disorder (PLMD) is estimated to occur in 5–8% of the paediatric population and 4–11% of the general adult population. Due to significant sleep fragmentation, PLMD can lead to functional impairment, including hyperactivity and delayed language development in children, and poor concentration and work performance in adults. Longitudinal data demonstrate that those with PLMD are at greater risk of depression and anxiety, and a 4-fold greater risk of developing dementia. PLMD has been extensively studied over the past two decades, and several key insights into the genetic, pathophysiological, and neural correlates have been proposed. Amongst these proposals is the concept of separable PLM phenotypes, proposed on the basis of nocturnal features such as the ratio of limb movements and distribution throughout the night. PLM phenotype and presentation, however, varies significantly depending on the scoring utilized and the nocturnal features examined, across age, and co-morbid clinical conditions. Furthermore, associations between these phenotypes with major neurologic and psychiatric disorders remain controversial. Methods: In order to elucidate potential divergent biological pathways that may help clarify important new treatment modalities, this paper utilizes narrative review and evaluates the evidence linking PLM motor patterns and phenotypes with hypothesised underlying patho-mechanisms. Distinctive, underlying patho-mechanisms include: a pure motor mechanism originating in the spinal cord, iron deficiency, dopamine system dysfunction, thalamic glutamatergic hyperactivity, and a more cortical-subcortical interplay. In support of the latter hypothesis, PLM rhyth

Published
2021

28. Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia

Author

Altmann, A., Cash, D. M., Bocchetta, M., Heller, C., Reynolds, R., Moore, K., Convery, R. S., Thomas, D. L., Van Swieten, J. C., Moreno, F., Sanchez-Valle, R., Borroni, B., Laforce, R., Masellis, M., Tartaglia, M. C., Graff, C., Galimberti, D., Rowe, J. B., Finger, E., Synofzik, M., Vandenberghe, R., De Mendonca, A., Tagliavini, F., Santana, I., Ducharme, S., Butler, C. R., Gerhard, A., Levin, J., Danek, A., Frisoni, G., Ghidoni, R., Sorbi, S., Otto, M., Ryten, M., Rohrer, J. D., Greaves, C., Peakman, G., Shafei, R., Todd, E., Rossor, M. N., Warren, J. D., Fox, N. C., Zetterberg, H., Guerreiro, R., Bras, J., Nicholas, J., Mead, S., Jiskoot, L., Meeter, L., Panman, J., Papma, J. M., Van Minkelen, R., Pijnenburg, Y., Barandiaran, M., Indakoetxea, B., Gabilondo, A., Tainta, M., De Arriba, M., Gorostidi, A., Zulaica, M., Villanua, J., Diaz, Z., Borrego-Ecija, S., Olives, J., Llado, A., Balasa, M., Antonell, A., Bargallo, N., Premi, E., Cosseddu, M., Gazzina, S., Padovani, A., Gasparotti, R., Archetti, S., Black, S., Mitchell, S., Rogaeva, E., Freedman, M., Keren, R., Tang-Wai, D., Oijerstedt, L., Andersson, C., Jelic, V., Thonberg, H., Arighi, A., Fenoglio, C., Scarpini, E., Fumagalli, G., Cope, T., Timberlake, C., Rittman, T., Shoesmith, C., Bartha, R., Rademakers, R., Wilke, C., Karnarth, H. -O., Bender, B., Bruffaerts, R., Van Damme, P., Vandenbulcke, M., Ferreira, C. B., Miltenberger, G., Maruta, C., Verdelho, A., Afonso, S., Taipa, R., Caroppo, P., Di Fede, G., Giaccone, G., Prioni, S., Redaelli, V., Rossi, G., Tiraboschi, P., Duro, D., Almeida, M. R., Castelo-Branco, M., Leitao, M. J., Tabuas-Pereira, M., Santiago, B., Gauthier, S., Rosa-Neto, P., Veldsman, M., Thompson, P., Langheinrich, T., Prix, C., Hoegen, T., Wlasich, E., Loosli, S., Schonecker, S., Semler, E., Anderl-Straub, S., Benussi, L., Binetti, G., Pievani, M., Lombardi, G., Nacmias, B., Ferrari, C., Bessi, V., Polito, C., Rowe, James [0000-0001-7216-8679], Apollo - University of Cambridge Repository, Medical Research Council, and Genetic FTD Initiative, GENFI

Subjects
0301 basic medicine, Cell type, Imaging genetics, Clinical Neurology, Medizin, Biology, Article, DISEASE, 03 medical and health sciences, 0302 clinical medicine, Atrophy, atrophy, C9orf72, Gene expression, medicine, Astrocytes, Frontotemporal dementia, ddc:610, 10. No inequality, Gene, 030304 developmental biology, Genetics, 0303 health sciences, Science & Technology, TREM2, AcademicSubjects/SCI01870, Neurodegeneration, General Engineering, C9orf72 Gene, Neurosciences, astrocytes, Genetic FTD Initiative, GENFI, medicine.disease, C9orf72 Protein, 030104 developmental biology, gene expression, imaging genetics, Original Article, AcademicSubjects/MED00310, Human medicine, Neurosciences & Neurology, Life Sciences & Biomedicine, 030217 neurology & neurosurgery
Abstract

Frontotemporal dementia is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of frontotemporal dementia, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work, we combined gene expression data for 16 772 genes from the Allen Institute for Brain Science atlas with brain maps of grey matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic Frontotemporal dementia Initiative study. No significant association was seen between C9orf72, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. After adjusting for spatial autocorrelation, between 1000 and 5000 genes showed a negative or positive association with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9Orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9Orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative association with genes involved in mitochondrial function, and a positive association with genes involved in vascular and glial cell function in each of the genetic groups. A set of 423 and 700 genes showed significant positive and negative association, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in frontotemporal dementia than previously assumed, and in the case of the positively associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood–brain barrier, respectively., Altmann et al. investigated the concordance between spatial cortical gene expression in healthy subjects and atrophy patterns in genetic frontotemporal dementia. They found that elevated gene expression of endothelial cell and astrocyte-related genes in regions with atrophy, suggesting a role of these cell types in the aetiology of frontotemporal dementia., Graphical Abstract Graphical Abstract

Published
2020
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29. ExploreQC: A toolbox for MRI quality control in the EPAD multicentre study

Author

Lorenzini, L., Ingala, S., Wottschel, V., Wink, A. M., Kuijer, J., Sudre, C. H., Haller, S., Molinuevo, J. L., Gispert, J. D., Cash, D. M., Thomas, D. L., Vos, S., Petr, J., Wolz, R., Pernet, C., Waldman, A., Barkhof, F., Mutsaerts, H. J. M. M., and Epad, C.

Abstract

Magnetic Resonance Imaging (MRI) of the brain is prone to artefacts that may worsen image quality and subsequent analyses. Despite the growing number of large-scale multi-institutional imaging studies, standardized approaches for defining inclusion and exclusion criteria on the basis of image data quality are still lacking and quality assessment is often based on visual inspection. We introduce ExploreQC, a MATLAB-based toolbox which implements a semi-automatic pipeline to assess QC metrics, select the most relevant parameters, and to derive informed inclusion thresholds.

Published
2020

30. Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia

Author

van der Ende, Emma, Xiao, MF, Xu, DS, Poos, Jackie, Panman, Jessica, Jiskoot, Lize, Meeter, Lieke, Dopper, Elise, Papma, Janne, Heller, C, Convery, H, Moore, K, Bocchetta, M, Neason, M, Peakman, G, Cash, D, Teunissen, CE, Graff, C, Synofzik, M, Moreno, F, Finger, E, Sanchez-Valle, R, Vandenberghe, R, Laforce, R, Jr, Masellis, M, Carmela Tartaglia, M, Rowe, JB, Butler, CR, Ducharme, S, Gerhard, A, Danek, A, Levin, J, Pijnenburg, YAL, Otto, M, Borroni, B, Tagliavini, F, De Mendonca, A, Santana, I, Galimberti, D, Seelaar, Harro, Rohrer, JD, Worley, PF, van Swieten, J.C., van der Ende, Emma, Xiao, MF, Xu, DS, Poos, Jackie, Panman, Jessica, Jiskoot, Lize, Meeter, Lieke, Dopper, Elise, Papma, Janne, Heller, C, Convery, H, Moore, K, Bocchetta, M, Neason, M, Peakman, G, Cash, D, Teunissen, CE, Graff, C, Synofzik, M, Moreno, F, Finger, E, Sanchez-Valle, R, Vandenberghe, R, Laforce, R, Jr, Masellis, M, Carmela Tartaglia, M, Rowe, JB, Butler, CR, Ducharme, S, Gerhard, A, Danek, A, Levin, J, Pijnenburg, YAL, Otto, M, Borroni, B, Tagliavini, F, De Mendonca, A, Santana, I, Galimberti, D, Seelaar, Harro, Rohrer, JD, Worley, PF, and van Swieten, J.C.

Published
2020

31. Peripheral Oxidative Stress Markers Are Related To Vascular Risk Factors And Subcortical Small Vessel Disease

Author

Warrick, N., Seitz, D., Prorok, J., Shawcross, D., Mahootchi, T., Esensoy, A., Yu, D., Danieli, E., Pushpakumar, D., Tony, J., Jacob, K., Dong, J., Javed, F., D’Souza, A., Mollayeva, T., Colantonio, A., Schulz, M., Burhan, A., Naidu, A. Srinivasan, Sarquis-Adamson, Y., Montero-Odasso, M., Cooper, N., Sekhon, H., Launay, C., Allali, G., Chabot, J., Beauchet, O., Watson, B., Lin, T., Korczak, A., Bartha, C., Best, S., Truemner, J., Borrie, M., Cammer, A., Whiting, S., Morgan, D., Newman, K., Duong, J. A., Mok, A., Wang, A. H., Lavoie, M., Bier, N., Macoir, J., Adlimoghaddam, A., Turner, R. S., Cadonic, C., Albensi, B. C., Davis, J., Lewis, V.-L., Pacione, J., Skanes, C., Feltz, N., Loncar, A., Naglie, G., Sanford, S., Stasiulis, E., Rapoport, M., Vrkljan, B., Tuokko, H., Porter, M., Polgar, J., Moorhouse, P., Mazer, B., Marshall, S., Gelinas, I, Crizzle, A, Belchior, P., Bedard, M, Kokorelias, K., Cameron, J., Gignac, M., Bechard, L., Beaton, D., McGilton, K.A., Tartaglia, M. C., Black, S., Mirza, S., Mutsaerts, H.-J., Cash, D., Bocchetta, M., Thomas, D., Dick, K., van Swieten, J., Borroni, B., Galimberti, D., Rowe, J., Bethell, J., Pringle, D., Commisso, E., Chambers, L., Cohen, C., Cowan, K., Fehr, P., Szeto, P., McGilton, K., Shaw, C., Okamura, H., Otani, M., Shimoyama, N., Fujii, T., Lusk, J., Punzalan, M., Dove, E., Cotnam, K., Astell, A., Chow, A. Froehlich, Bayly, M., Kosteniuk, J., Elliot, V., O’Connell, M. E., Kirk, A., Stewart, N., Holroyd-Leduc, J., Daku, J., Kennett-Russill, D., Hack, T., Dilara, A., Astell, A. J., Hernandez, A., Divine, A., Hunter, S., Jacova, C., Alexander, C., Joseph, J. T., Alvarez, A., Smith, E., Woo, S. M. S., Chan, P., Wilkins-Ho, M., Blackburn, P., Fernando, N., Mehra, A., Vasser, E., Musacchio, M., Waxman, R., Fischler, I., Ghaffar, O., DeBay, D. R., Macdonald, I. R., Reid, G. A., Pottie, I. R., Maxwell, S. P., Cash, M. K., Martin, E., Bowen, C. V., Darvesh, S., MacPhee, J., Jorgensen, M., Fogarty, J., Phillips, N., Diprospero, C., Parent, A., Whitehead, V., Campbell, T., Mohades, Z., Chertkow, H., Wong, S., Wilchesky, M., McCusker, J., Champoux, N., Vu, T.T. M., Ciampi, A., Monette, J., Lungu, O., Ballard, S. A., Belzile, E., Carmichael, P.-H., Voyer, P., Cetin-Sahin, D., Gore, B., Peretti, M., Gore, G., Landry, V., Yetman, L., MacDonald, E., McGibbon, C., MacNeil, D., Jarrett, P., Iaboni, A., Andrews, J., Hafezi, S., Marshall, C., Tsokas, M., Martin, L. Schindel, Van Ooteghem, K., Mansfield, A., Marcil, M., Gold, D., Musselman, K., Flint, A., Finger, E., Feldman, H., Cummings, J., Coleman, K., Boxer, A., Berry, S., Hsiung, R., Curtis, A., Zhang, K., Davidson, H. R., Boccone, G., Camicioli, R., Masellis, M., Tierney, M., Dolatabadi, E., Taati, B., Jonas-Simpson, C., Donovan, L., Cross, N., Keren, R., Shan, R., Holley, J., Waisman, Z., Katchaluba, J., Wimhurst, C., Steele, M., Loganathan, P., Gural, P., Shearer, T., Reardon, J., Pilgrim, J., Pitawanakwat, K., Jones, L., Piriano, E., Blind, M., Otowadjiwan, J., Makela, R., Spicer, B., Bretzlaff, M., Jacklin, K., McKay, Kristy, Graham, N., Tang-Wai, D., Leonard, C., Mitchell, S., Laird, L., Rochon, E., Maclagan, L., Maxwell, C., Guan, J., Campitelli, M., Herrmann, N., Lapane, K., Hogan, D., Amuah, J., Gill, S., Bronskill, S., Ebert, P., Kwok, J., Watt, A., Garrett, S., Hoefling, L., Ellery, C., Leggieri, M., Fornazzari, L., Thaut, M., Munoz, D., Barfett, J., Fischer, C., Schweizer, T., Yogaparan, T., Dallaire-Théroux, C., Potvin, O., Dieumegarde, L., Duchesne, Simon, Amini, A.E. Ebrahim, Amini, A.Z. Ebrahim, Dao, E., Barha, C. K., Best, J. R., Hsiung, G.-Y. R., Tam, R., Liu-Ambrose, T., Sztramko, R., Wurster, A., Papaiouannou, A., Cowan, D., St. Onge, J., Allaby, C., Harrison, L., Cimino, C., Marr, S., Patterson, C., Woo, T., Levinson, A., Fisher, S., Mojaverian, N., Hsu, A., Taljaard, M., Manuel, D., Tanuseputro, P., Park, E., Liu, L., VanderPloeg, K., Black, A., Bartha, R., Rabin, J., Yang, H.-S., Schultz, A., Hanseeuw, B., Marshall, G., Hedden, T., Rentz, D., Johnson, K., Sperling, R., Chhatwal, J., Desmarais, P., Miville, C., Keith, J., Lanctôt, K., Thomas, N., Mattek, N., Riley, T., Witter, P., Reynolds, C., Austin, J., Sharma, N., Kaye, J., Bechard, L. E., Mitchell, C. M., Regan, K., Bergelt, M. D., Middleton, L.E., Hewston, P., Kennedy, C., Merom, D., Trainor, L., Grenier, A., Ioannidis, G., Lee, J., Papaioannou, A., Qian, W., Churchill, N., Kumar, S., Rajji, T., Ojeda-López, C., Milán-Tomás, Á., Lam, B., Gao, F. Q., Cumberbatch, S., Gies, S., Tomas, A. Milan, Ojeda-Lopez, C., Lim, A. S., Black, S. E., Sharma, M. J., Ramirez, J., Holmes, M. F., Gao, F., Varatharajah, B., Yhap, V., Appel, L., Bogler, O., Appel, E., Wiseman, M., Cohen, L., Hill, D., Abrams, H., Campos, J., Sapkota, S., Adamo, S., Stuss, D. T., Martinez, M., Multani, N., Anor, C. J., Fox, S., Lang, A. E., Marras, C., Compagnone, J., Li, J., Freedman, M., Kleiner-Fisman, G., Kennedy, J., Chen, R., Lang, A., Sévigny-Dupont, P., Bocti, C., Joannette, M., Lavallée, M. M., Joubert, S., Knoefel, F., Goubran, R., Baker, A., Fraser, S., Allard, B., Wallace, B., Stroulia, E., Guana, V., Masson, P., Alli, S., Kolla, N., De Luca, V., Bouvier, L., Monetta, L., Vitali, P., Laforce, R., Martel-Sauvageau, V., Talebzadeh, A., Ashourinia, K., Moy, S., Lake, A., Cockburn, A., Krisman, D., Sadasivan, B., Sit, W., Stoops, S., McCurbin, S., Cullen, S., Carroll, S., Tasmim, S., Kapoor, E., Callahan, B., Sharma, M., Bierstone, D., Stuss, D., Kapadia, M., Mian, F., Ma, D., Rosa, E., Michalski, B., Zovkic, I., Forsythe, P., Sakic, B., Fahnestock, M., Baxter, J., Peloso, S., Tung, J., Cox, L., Benjamin, S., An, H., Ho, J., Turcotte, V., Parent, C., Gauthier-Beaupré, A., Biss, R., Sultana, A., Chu, C. H., Sun, W., Bartfay, E., Smye, V., Newton, D., Pepin, M., Biswas, S., Madahey, H., Crawford, S. J., Gutmanis, I., Blake, C., Duchesne, S., Hudon, C., Mah, L., Ali, A., Shorey, C., Szabuniewicz, C. M., Anderson, N. D., Verhoeff, N. P. L. G., Cheers, S., Penko, M., Gevaert, V., Yang, Y., Law, J., Modarresi, S., Grahn, J., Overend, T., Amini, D., Thiruparanathan, T., Cheung, T., Iskandar, S., Arone, Y., Young, C., Berezuk, C., and Zakzanis, K.

Subjects
Abstracts
Published
2018

32. Gamma shielding materials for MR-compatible PET

Author

Strul, D., Cash, D., Keevil, S.F., Halsted, P., Williams, S.C.R., and Marsden, P.K.

Subjects
Nuclear research -- Analysis, Gamma rays -- Usage, Magnetic resonance imaging -- Equipment and supplies, PET imaging -- Methods, Nonferrous metals, Metallic oxides, Business, Electronics, Electronics and electrical industries
Abstract

As for standard positron emission tomography (PET) scanners, MR-compatible PET scanners will require gamma shielding to suppress the influence of activity outside the PET field of view (FOV). Suitable materials must have very specific properties, including magnetic properties close to those of water, high density, high atomic number, and ideally a low conductivity. In order to identify potential suitable materials, we have selected several heavy-metal-based candidates based on the available data for magnetic and shielding properties. These materials include several nonferromagnetic metals and metal oxides, two scintillating crystals (bismuth germanate and lead tungstate) and two metal/epoxy compounds. The magnetic resonance imaging (MRI) compatibility of these materials was assessed under various conditions, both on a human and a small-animal MRI scanner. In parallel, we assessed the shielding efficiency at 661 kev of the most promising candidates. These experiments showed that there is a range of possibilities for the design of MR-compatible gamma shields. Lead has acceptable magnetic compatibility but can induce significant conductivity-related artefacts. Heavy-metal-based minerals are fully insulating and hot-pressed lead monoxide showed good MR compatibility combined with good shielding properties. Other possibilities include the use of lead based powders and heavy-metal oxide composites. Index Terms--Magnetic resonance imaging (MRI), positron emission tomography (PET), shielding.

Published
2003

35. Causally Probing the Role of the Hippocampus in Fear Discrimination: A Precision Functional Mapping–Guided, Transcranial Magnetic Stimulation Study in Participants With Posttraumatic Stress Symptoms

Author

Ryan D. Webler, Cristian Morales Carrasco, Samuel E. Cooper, Mo Chen, Christopher O. Hunt, Sierra Hennessy, Lancy Cao, Carol Lam, Allen Chiu, Cash Differding, Erin Todd, Timothy J. Hendrickson, Desmond J. Oathes, Alik S. Widge, Robert J.M. Hermosillo, Steven M. Nelson, Damien A. Fair, Shmuel M. Lissek, and Ziad Nahas

Subjects
Fear conditioning, Fear generalization, Hippocampal network–targeted TMS, Hippocampus, Precision functional mapping, TMS, Psychiatry, RC435-571
Abstract

Background: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network–targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: β = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: β = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.

Published
2024
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40. Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study

Author

Mutsaerts, H. J. M. M., Mirza, S. S., Petr, J., Thomas, D. L., Cash, D. M., Bocchetta, M., De Vita, E., Metcalfe, A. W. S., Shirzadi, Z., Robertson, A. D., Tartaglia, M. C., Mitchell, S. B., Black, S. E., Freedman, M., Tang-Wai, D., Keren, R., Rogaeva, E., Van Swieten, J., Laforce, R., Tagliavini, F., Borroni, B., Galimberti, D., Rowe, J. B., Graff, C., Frisoni, G. B., Finger, E., Sorbi, S., De Mendonca, A., Rohrer, J. D., Macintosh, B. J., Masellis, M., Andersson, C., Archetti, S., Arighi, A., Benussi, L., Binetti, G., Cosseddu, M., Dick, K. M., Fallstrom, M., Ferreira, C., Fenoglio, C., Fox, N. C., Fumagalli, G., Gazzina, S., Ghidoni, R., Grisoli, M., Jelic, V., Jiskoot, L., Lombardi, G., Maruta, C., Mead, S., Meeter, L., Van Minkelen, R., Nacmias, B., Oijerstedt, L., Ourselin, S., Padovani, A., Panman, J., Pievani, M., Polito, C., Premi, E., Prioni, S., Rademakers, R., Redaelli, V., Rossi, G., Rossor, M. N., Scarpini, E., Thonberg, H., Tiraboschi, P., Verdelho, A., Warren, J. D., Rowe, James [0000-0001-7216-8679], Apollo - University of Cambridge Repository, Neurology, Amsterdam Neuroscience - Neurodegeneration, and Radiology and Nuclear Medicine

Subjects
0301 basic medicine, Male, Pathology, Tau Proteins/genetics, cerebral blood flow, Gene mutation, Neuropsychological Tests, Arterial spin labelling, Frontotemporal Dementia/genetics, 0302 clinical medicine, Progranulins, C9orf72, Brain, Middle Aged, Corrigenda, Magnetic Resonance Imaging, Cerebral blood flow, Cerebrovascular Circulation, Frontotemporal Dementia, Female, arterial spin labelling, Frontotemporal dementia, Adult, medicine.medical_specialty, Heterozygote, genetic frontotemporal dementia, presymptomatic biomarker, C9orf72 Protein/genetics, tau Proteins, Progranulins/genetics, 03 medical and health sciences, Neuroimaging, mental disorders, medicine, Brain/metabolism, Dementia, Humans, Cerebral perfusion pressure, Aged, C9orf72 Protein, business.industry, Original Articles, Voxel-based morphometry, medicine.disease, arterial spin labeling, ddc:616.8, Genetic frontotemporal dementia, Presymptomatic biomarker, 030104 developmental biology, Cross-Sectional Studies, Mutation, Neurology (clinical), business, 030217 neurology & neurosurgery, Cerebrovascular Circulation/genetics
Abstract

Imaging biomarkers are needed to detect early brain changes in presymptomatic carriers harbouring FTD mutations. Using arterial spin labelling-MRI, Mutsaerts, Mirza et al. identify an inverse association between cerebral perfusion in frontotemporoparietal regions and expected age of onset. Cerebral perfusion may be a promising imaging biomarker for presymptomatic genetic FTD., Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

Published
2019
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41. Inflammatory biomarkers in Alzheimer's disease plasma

Author

Leckey, C, Nevado-Holgado, AJ, Barkhof, F, Bertram, L, Blin, O, Bos, I, Dobricic, V, Engelborghs, S, Frisoni, G, Frolich, L, Gabel, S, Johannsen, P, Kettunen, P, Koszewska, I, Legido-Quigley, C, Lleo, A, Martinez-Lage, P, Mecocci, P, Meersmans, K, Molinuevo, JL, Peyratout, G, Popp, J, Richardson, J, Sala, I, Scheltens, P, Streffer, J, Soininen, H, Tainta-Cuezva, M, Teunissen, C, Tsolaki, M, Vandenberghe, R, Visser, PJ, Vos, S, Wahlund, LO, Wallin, A, Westwood, S, Zetterberg, H, Bullmore, ET, Bhatti, J, Chamberlain, SJ, Correia, MM, Crofts, AL, Dickinson, A, Foster, AC, Kitzbichler, MG, Knight, C, Lynall, ME, Maurice, C, O'Donnell, C, Pointon, LJ, Hyslop, PS, Turner, L, Vertes, P, Widmer, B, Williams, GB, Morgan, BP, Morgan, AR, O'Hagan, C, Touchard, S, Cavanagh, J, Deith, C, Farmer, S, McClean, J, McColl, A, McPherson, A, Scouller, P, Sutherland, M, Boddeke, HWGM, Richardson, JC, Khan, S, Murphy, P, Parker, CA, Patel, J, Jones, D, Boer, P, Kemp, J, Drevets, WC, Nye, JS, Wittenberg, G, Isaac, J, Bhattacharya, A, Carruthers, N, Kolb, H, Pariante, CM, Turkheimer, F, Barker, GJ, Byrom, H, Cash, D, Cattaneo, A, Gee, A, Hastings, C, Mariani, N, McLaughlin, A, Mondelli, V, Nettis, M, Nikkheslat, N, Randall, K, Sheridan, H, Simmons, C, Singh, N, Van Loo, V, Vicente-Rodriguez, M, Wood, TC, Worrell, C, Zajkowska, Z, Plath, N, Egebjerg, J, Eriksson, H, Gastambide, F, Adams, KH, Jeggo, R, Thomsen, C, Pederson, JT, Campbell, B, Moller, T, Nelson, B, Zorn, S, O'Connor, J, Attenburrow, MJ, Baird, A, Benjamin, J, Clare, S, Cowen, P, Huang, IS, Hurley, S, Jones, H, Lovestone, S, Mada, F, Nevado-Holgado, A, Oladejo, A, Ribe, E, Smith, K, Vyas, A, Hughes, Z, Balice-Gordon, R, Duerr, J, Piro, JR, Sporn, J, Perry, VH, Cleal, M, Fryatt, G, Gomez-Nicola, D, Mancuso, R, Reynolds, R, Harrison, NA, Cercignani, M, Clarke, CL, Hoskins, E, Kohn, C, Murray, R, Wilcock, L, Wlazly, D, NIMA Consortium, and NIMA-Wellcome Trust Consortium

Subjects
Inflammation, Plasma, Complement, Biomarker, Alzheimer's disease
Abstract

Introduction: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a "Holy Grail" of AD research and intensively sought; however, there are no well-established plasma markers. Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOe4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Published
2019

44. Comparison of arterial spin labeling registration strategies in the multi-center GENetic frontotemporal dementia initiative (GENFI)

Author

Mutsaerts, H. J. M. M., Petr, J., Thomas, D. L., De Vita, E., Cash, D. M., van Osch, M. J. P., Golay, X., Groot, P. F. C., Ourselin, S., van Swieten, J., Laforce, R., Tagliavini, F., Borroni, B., Galimberti, D., Rowe, J. B., Graff, C., Pizzini, F. B., Finger, E., Sorbi, S., Castelo Branco, M., Rohrer, J. D., Masellis, M., Macintosh, B. J., Rossor, M., Fox, N., Warren, J., Bocchetta, M., Dick, K., Pievani, M., Ghidoni, R., Benussi, L., Padovani, A., Cosseddu, M., Mendonca, A., Frisoni, G., Premi, E., Archetti, S., Scarpini, E., Fumagalli, G., Arighi, A., Fenoglio, C., Prioni, S., Redaelii, V., Grisoli, M., Tiraboschi, P., Black, S., Rogaeva, E., Freedman, M., Tartaglia, M. C., Tang-Wai, D., Keren, R., Panman, J., Meeter, L., Jiskoot, L., van Minkelen, R., Lombardi, G., Polito, C., Nacmias, B., Jelic, V., Andersson, C., Oijerstedt, L., Fallstrom, M., Thonberg, H., Verdelho, A., Maruta, C., Neurology, Mutsaerts, Henri JMM [0000-0003-0894-0307], Apollo - University of Cambridge Repository, and Other departments

Subjects
Adult, Male, cerebral blood flow, Brain, Reproducibility of Results, Arteries, Middle Aged, arterial spin labeling, Magnetic Resonance Imaging, Article, Perfusion, image registration, Young Adult, Imaging, Three-Dimensional, Cerebrovascular Circulation, Frontotemporal Dementia, Image Processing, Computer-Assisted, Humans, Female, Spin Labels, Gray Matter
Abstract

PURPOSE: To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w) images, with the goal of reducing the between-subject variability of cerebral blood flow (CBF) images. MATERIALS AND METHODS: Multi-center 3T ASL data were collected at eight sites with four different sequences in the multi-center GENetic Frontotemporal dementia Initiative (GENFI) study. In a total of 48 healthy controls, we compared the following image registration options: (I) which images to use for registration (perfusion-weighted images [PWI] to the segmented gray matter (GM) probability map (pGM) (CBF-pGM) or M0 to T1w (M0-T1w); (II) which transformation to use (rigid-body or non-rigid); and (III) whether to mask or not (no masking, M0-based FMRIB software library Brain Extraction Tool [BET] masking). In addition to visual comparison, we quantified image similarity using the Pearson correlation coefficient (CC), and used the Mann-Whitney U rank sum test. RESULTS: CBF-pGM outperformed M0-T1w (CC improvement 47.2% ± 22.0%; P < 0.001), and the non-rigid transformation outperformed rigid-body (20.6% ± 5.3%; P < 0.001). Masking only improved the M0-T1w rigid-body registration (14.5% ± 15.5%; P = 0.007). CONCLUSION: The choice of image registration strategy impacts ASL group analyses. The non-rigid transformation is promising but requires validation. CBF-pGM rigid-body registration without masking can be used as a default strategy. In patients with expansive perfusion deficits, M0-T1w may outperform CBF-pGM in sequences with high effective spatial resolution. BET-masking only improves M0-T1w registration when the M0 image has sufficient contrast. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:131-140.

Published
2018
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45. Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

Author

Young, A. L., Marinescu, R. V., Oxtoby, N. P., Bocchetta, M., Yong, K., Firth, N. C., Cash, D. M., Thomas, D. L., Dick, K. M., Cardoso, J., van Swieten, J., Borroni, B., Galimberti, D., Masellis, M., Tartaglia, M. C., Rowe, J. B., Graff, C., Tagliavini, F., Frisoni, G. B., Laforce, R., Finger, E., de Mendonca, A., Sorbi, S., Warren, J. D., Crutch, S., Fox, N. C., Ourselin, S., Schott, J. M., Rohrer, J. D., Alexander, D. C., Andersson, C., Archetti, S., Arighi, A., Benussi, L., Binetti, G., Black, S., Cosseddu, M., Fallstrom, M., Ferreira, C., Fenoglio, C., Freedman, M., Fumagalli, G. G., Gazzina, S., Ghidoni, R., Grisoli, M., Jelic, V., Jiskoot, L., Keren, R., Lombardi, G., Maruta, C., Meeter, L., Mead, S., van Minkelen, R., Nacmias, B., Oijerstedt, L., Padovani, A., Panman, J., Pievani, M., Polito, C., Premi, E., Prioni, S., Rademakers, R., Redaelli, V., Rogaeva, E., Rossi, G., Rossor, M., Scarpini, E., Tang-Wai, D., Thonberg, H., Tiraboschi, P., Verdelho, A., Weiner, M. W., Aisen, P., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J. Q., Toga, A. W., Beckett, L., Green, R. C., Saykin, A. J., Morris, J., Shaw, L. M., Khachaturian, Z., Sorensen, G., Kuller, L., Raichle, M., Paul, S., Davies, P., Fillit, H., Hefti, F., Holtzman, D., Mesulam, M. M., Potter, W., Snyder, P., Schwartz, A., Montine, T., Thomas, R. G., Donohue, M., Walter, S., Gessert, D., Sather, T., Jiminez, G., Harvey, D., Bernstein, M., Thompson, P., Schuff, N., Borowski, B., Gunter, J., Senjem, M., Vemuri, P., Jones, D., Kantarci, K., Ward, C., Koeppe, R. A., Foster, N., Reiman, E. M., Chen, K., Mathis, C., Landau, S., Cairns, N. J., Householder, E., Taylor-Reinwald, L., Lee, V., Korecka, M., Figurski, M., Crawford, K., Neu, S., Foroud, T. M., Potkin, S., Shen, L., Faber, K., Kim, S., Nho, K., Thal, L., Buckholtz, N., Albert, M., Frank, R., Hsiao, J., Kaye, J., Quinn, J., Lind, B., Carter, R., Dolen, S., Schneider, L. S., Pawluczyk, S., Beccera, M., Teodoro, L., Spann, B. M., Brewer, J., Vanderswag, H., Fleisher, A., Heidebrink, J. L., Lord, J. L., Mason, S. S., Albers, C. S., Knopman, D., Johnson, K., Doody, R. S., Villanueva-Meyer, J., Chowdhury, M., Rountree, S., Dang, M., Stern, Y., Honig, L. S., Bell, K. L., Ances, B., Carroll, M., Leon, S., Mintun, M. A., Schneider, S., Oliver, A., Marson, D., Griffith, R., Clark, D., Geldmacher, D., Brockington, J., Roberson, E., Grossman, H., Mitsis, E., de Toledo-Morrell, L., Shah, R. C., Duara, R., Varon, D., Greig, M. T., Roberts, P., Onyike, C., D'Agostino, D., Kielb, S., Galvin, J. E., Cerbone, B., Michel, C. A., Rusinek, H., de Leon, M. J., Glodzik, L., De Santi, S., Doraiswamy, P. M., Petrella, J. R., Wong, T. Z., Arnold, S. E., Karlawish, J. H., Wolk, D., Smith, C. D., Jicha, G., Hardy, P., Sinha, P., Oates, E., Conrad, G., Lopez, O. L., Oakley, M. A., Simpson, D. M., Porsteinsson, A. P., Goldstein, B. S., Martin, K., Makino, K. M., Ismail, M. S., Brand, C., Mulnard, R. A., Thai, G., Mc-Adams-Ortiz, C., Womack, K., Mathews, D., Quiceno, M., Diaz-Arrastia, R., King, R., Weiner, M., Martin-Cook, K., Devous, M., Levey, A. I., Lah, J. J., Cellar, J. S., Burns, J. M., Anderson, H. S., Swerdlow, R. H., Apostolova, L., Tingus, K., Woo, E., Silverman, D. H., P. H., Lu, Bartzokis, G., Graff-Radford, N. R., Parfitt, F., Kendall, T., Johnson, H., Farlow, M. R., Hake, A. M., Matthews, B. R., Herring, S., Hunt, C., van Dyck, C. H., Carson, R. E., Macavoy, M. G., Chertkow, H., Bergman, H., Hosein, C., Stefanovic, B., Caldwell, C., Hsiung, G. -Y. R., Feldman, H., Mudge, B., Assaly, M., Kertesz, A., Rogers, J., Bernick, C., Munic, D., Kerwin, D., Mesulam, M. -M., Lipowski, K., C. -K., Wu, Johnson, N., Sadowsky, C., Martinez, W., Villena, T., Turner, R. S., Reynolds, B., Sperling, R. A., Johnson, K. A., Marshall, G., Frey, M., Lane, B., Rosen, A., Tinklenberg, J., Sabbagh, M. N., Belden, C. M., Jacobson, S. A., Sirrel, S. A., Kowall, N., Killiany, R., Budson, A. E., Norbash, A., Johnson, P. L., Allard, J., Lerner, A., Ogrocki, P., Hudson, L., Fletcher, E., Carmichael, O., Olichney, J., Decarli, C., Kittur, S., Borrie, M., Lee, T. -Y., Bartha, R., Johnson, S., Asthana, S., Carlsson, C. M., Potkin, S. G., Preda, A., Nguyen, D., Tariot, P., Reeder, S., Bates, V., Capote, H., Rainka, M., Scharre, D. W., Kataki, M., Adeli, A., Zimmerman, E. A., Celmins, D., Brown, A. D., Pearlson, G. D., Blank, K., Anderson, K., Santulli, R. B., Kitzmiller, T. J., Schwartz, E. S., Sink, K. M., Williamson, J. D., Garg, P., Watkins, F., Ott, B. R., Querfurth, H., Tremont, G., Salloway, S., Malloy, P., Correia, S., Rosen, H. J., Miller, B. L., Mintzer, J., Spicer, K., Bachman, D., Pasternak, S., Rachinsky, I., Drost, D., Pomara, N., Hernando, R., Sarrael, A., Schultz, S. K., Ponto, L. L. B., Shim, H., Smith, K. E., Relkin, N., Chaing, G., Raudin, L., Smith, A., Fargher, K., Raj, B. A., Neylan, T., Grafman, J., Davis, M., Morrison, R., Hayes, J., Finley, S., Friedl, K., Fleischman, D., Arfanakis, K., James, O., Massoglia, D., Fruehling, J. J., Harding, S., Peskind, E. R., Petrie, E. C., Li, G., Yesavage, J. A., Taylor, J. L., and Furst, A. J.

Published
2018

47. Obstructive Sleep Apnoea and Alzheimer’s Disease: in Search of Shared Pathomechanisms

Author

Polsek, D., Gildeh, N., Cash, D., Winsky-Sommerer, R., Williams, S.C.R., Turkheimer, F., Leschziner, G.D., Morrell, M.J., and Rosenzweig, I.

Subjects
Inflammation, Sleep Wake Disorders, Sleep Apnea, Obstructive, Neuroinflammation, Alzheimer Disease, Astrocytes, Humans, Obstructive sleep apnea, Alzheimer’s disease, Models, Biological, Article, respiratory tract diseases
Abstract

Highlights • Alzheimer’s disease (AD) is a significant public health concern. • The processes involved in the pathogenesis of AD are shown to overlap with those found in cognitive decline in Obstructive Sleep Apnoea (OSA). • An excessive and prolonged neuronal activity might contribute to genesis and acceleration of both AD and OSA. • External factors, such are systemic inflammation and obesity, can interfere with immunological processes of the brain, and promote disease progression., Alzheimer’s disease (AD) is a significant public health concern. The incidence continues to rise, and it is set to be over one million in the UK by 2025. The processes involved in the pathogenesis of AD have been shown to overlap with those found in cognitive decline in patients with Obstructive Sleep Apnoea (OSA). Currently, the standard treatment for OSA is Continuous Positive Airway Pressure. Adherence to treatment can, however, be an issue, especially in patients with dementia. Also, not all patients respond adequately, necessitating the use of additional treatments. Based on the body of data, we here suggest that excessive and prolonged neuronal activity might contribute to genesis and acceleration of both AD and OSA in the absence of appropriately structured sleep. Further, we argue that external factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain, and further promote disease progression. If this hypothesis is proven in future studies, it could have far-reaching clinical translational implications, as well as implications for future treatment strategies in OSA.

Published
2017
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48. Obstructive sleep apnoea and Alzheimer's disease: in search of shared pathomechanisms

Author

Polsek, D, Gildeh, N, Cash, D, Winsky-Sommerer, R, Williams, SCR, Turkheimer, F, Leschziner, GD, Morrell, MJ, and Rosenzweig, I

Subjects
MILD COGNITIVE IMPAIRMENT, INTERMITTENT HYPOXIA, DECLINE, ARCHITECTURE, Science & Technology, Neuroinflanunation, MEMORY, Neurosciences, BRAIN STRUCTURE, 11 Medical And Health Sciences, Alzheimer's disease, Behavioral Science & Comparative Psychology, Obstructive sleep apnea, RECEPTORS, 17 Psychology And Cognitive Sciences, Neuroinflammation, Astrocytes, EXTRACELLULAR-SPACE, CO-MORBIDITIES, Neurosciences & Neurology, Life Sciences & Biomedicine, Behavioral Sciences, NEURONS, Alzheimer’s disease
Abstract

Alzheimer’s disease (AD) is a significant public health concern. The incidence continues to rise, and it is set to be over one million in the UK by 2025. The processes involved in the pathogenesis of AD have been shown to overlap with those found in cognitive decline in patients with Obstructive Sleep Apnoea (OSA). Currently, the standard treatment for OSA is Continuous Positive Airway Pressure. Adherence to treatment can, however, be an issue, especially in patients with dementia. Also, not all patients respond adequately, necessitating the use of additional treatments. Based on the body of data, we here suggest that excessive and prolonged neuronal activity might contribute to genesis and acceleration of both AD and OSA in the absence of appropriately structured sleep. Further, we argue that external factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain, and further promote disease progression. If this hypothesis is proven in future studies, it could have far-reaching clinical translational implications, as well as implications for future treatment strategies in OSA.

Published
2017

50. GABAA receptor availability is not altered in adults with autism spectrum disorder or in mouse models

Author

Horder, J., Andersson, M., Mendez, M., Singh, N., Tangen, A., Lundberg, J., Gee, A., Halldin, C., Veronese, M., Bolte, Sven, Farde, L., Sementa, T., Cash, D., Higgins, K., Spain, D., Turkheimer, F., Mick, I., Selvaraj, S., Nutt, D., Lingford-Hughes, A., Howes, O., Murphy, D., Borg, J., Horder, J., Andersson, M., Mendez, M., Singh, N., Tangen, A., Lundberg, J., Gee, A., Halldin, C., Veronese, M., Bolte, Sven, Farde, L., Sementa, T., Cash, D., Higgins, K., Spain, D., Turkheimer, F., Mick, I., Selvaraj, S., Nutt, D., Lingford-Hughes, A., Howes, O., Murphy, D., and Borg, J.

Abstract

Copyright © 2018 The Authors, some rights reserved. Preliminary studies have suggested that -aminobutyric acid type A (GABAA) receptors, and potentially the GABAA 5 subtype, are deficient in autism spectrum disorder (ASD). However, prior studies have been confounded by the effects of medications, and these studies did not compare findings across different species. We measured both total GABAA and GABAA 5 receptor availability in two positron emission tomography imaging studies. We used the tracer [11C]flumazenil in 15 adults with ASD and in 15 control individuals without ASD and the tracer [11C]Ro15-4513 in 12 adults with ASD and in 16 control individuals without ASD. All participants were free of medications. We also performed autoradiography, using the same tracers, in three mouse models of ASD: the Cntnap2 knockout mouse, the Shank3 knockout mouse, and mice carrying a 16p11.2 deletion. We found no differences in GABAA receptor or GABAA 5 subunit availability in any brain region of adults with ASD compared to those without ASD. There were no differences in GABAA receptor or GABAA 5 subunit availability in any of the three mouse models. However, adults with ASD did display altered performance on a GABA-sensitive perceptual task. Our data suggest that GABAA receptor availability may be normal in adults with ASD, although GABA signaling may be functionally impaired.

Published
2018

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