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Macrophage inhibitory cytokine-1 is associated with cognitive impairment and predicts cognitive decline – The Sydney Memory and Aging Study
neurology, psychiatry and brain research 20 (2014) 3–27
immune responses observed in autoimmune neuroinflammatory disease. Here, we identify a novel pathway for immune cell traffic from the brain that is associated with the rostral migratory stream, best known as a forebrain source of newly generated neurons. Targeted pharmacologic interruption of this immune cell traffic, with Fingolimod, influences anti-CNS T-cell responses in the cervical lymph nodes (CxLNs) and modulates the severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. This treatment also induced EAE in a disease-resistant transgenic (MOG-TCR) mouse strain, by altering dendritic cell-mediated T-regulatory lymphocyte function in the CxLNs, breaking CNS immune tolerance. These data represent the first description of an immune cell pathway, originating in the CNS, capable of dampening anti-CNS immune responses in the periphery. These data provide mechanistic insight into why Fingolimod treatment might, in some cases, exacerbate CNS neuroinflammation. They further suggest that focal therapeutic interventions may selectively modify anti-CNS immunity. http://dx.doi.org/10.1016/j.npbr.2014.01.144 Macrophage inhibitory cytokine-1 is associated with cognitive impairment and predicts cognitive decline – The Sydney Memory and Aging Study T. Fuchs a, J.N. Trollor a,b, J. Crawford b, B.T. Baune c, K. Samaras d,e, L. Campbell d,e, S.N. Breit f, H. Brodaty b,g, P. Sachdev b,h, E. Smith a,b, D.A. Brown f,* a
Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Sydney, NSW 2010, Australia b Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW 2010, Australia c Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia d Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia e Department of Endocrinology, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia f St Vincent's Centre for Applied Medical Research, St Vincent's Hospital and University of New South Wales, Sydney, NSW 2010, Australia g Dementia Collaborative Research Centre, School of Psychiatry, University of New South Wales, Sydney, Australia h Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, NSW, Australia *Corresponding author. Higher levels of macrophage inhibitory cytokine-1, also known as growth differentiation factor 15 (MIC-1/GDF15), are associated with inflammatory disease, adverse health outcomes and all-cause mortality. This study examined the relationships between MIC-1/GDF15 serum levels and global cognition, five cognitive domains, and mild cognitive impairment (MCI), at baseline (Wave 1) and prospectively at 2 years (Wave 2), in non-demented participants aged 70–90 years. Analyses were controlled for age, sex, education, Framingham risk score, history of cerebrovascular accident, acute myocardial infarction, angina, cancer, depression, C-reactive protein, tumor necrosis factor-a, interleukins 6 and 12, and apolipoprotein e4 genotype. Higher MIC-1/GDF15 levels were significantly associated with lower global cognition at both waves. Crosssectional associations were found between MIC-1/GDF15 and all cognitive domains in Wave 1 (all P < 0.001) and between processing speed, memory, and executive function in Wave 2 (all P < 0.001). Only a trend was found for the prospective
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analyses, individuals with high MIC-1/GDF15 at baseline declined in global cognition, executive function, memory, and processing speed. However, when categorizing MIC-1/ GDF15 by tertiles, prospective analyses revealed statistically significant lower memory and executive function in Wave 2 in those in the upper tertile compared with the lower tertile. Receiver operating characteristics (ROC) analysis was used to determine MIC-1/GDF15 cutoff values associated with cognitive decline and showed that a MIC-1/GDF15 level exceeding 2764 pg/ml was associated with a 20% chance of decline from normal to MCI or dementia. In summary, MIC-1/GDF15 levels are associated with cognitive performance and cognitive decline. Further research is required to determine the pathophysiology of this relationship. http://dx.doi.org/10.1016/j.npbr.2014.01.145 Lymphopenia helps early diagnosis of systemic lupus erythematosus for patients with psychosis as an initial symptom Y. Chiba a,*, O. Katsuse a, H. Fujishiro a, A. Kamada a, T. Saito a, T. Ikura a, Y. Takahashi b, M. Kunii c, M. Takeno d, Y. Hirayasu a a
Department of Psychiatry, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan b Department of Pediatrics, Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama 886, Aoi-ku, Shizuoka 4208688, Japan c Department of Neurology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan d Department of Internal Medicine and Clinical Immunology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan *Corresponding author. Patients with systemic lupus erythematosus (SLE) frequently exhibit neuropsychiatric symptoms (neuropsychiatric SLE; NPSLE). Although some patients’ initial SLE symptoms are neuropsychiatric, it is difficult to diagnose them with SLE before the appearance of physical symptoms of SLE or relatively severe NP symptoms such as disturbance of consciousness or seizure. Hematological disorders are also frequent, even as the initial symptoms of SLE. Here we report two patients who presented with NP symptoms as initial symptoms of SLE, and lymphopenia was a useful symptom for the early diagnosis of SLE. Case 1 was a young woman with a past history of transient facial erythema. She suffered from psychosis, depression and mild cognitive impairment. Case 2 was a young woman who initially exhibited psychosis, mania and mild cognitive decline. Routine laboratory blood tests revealed lymphopenia, and additional blood tests revealed elevated antinuclear antibodies and antidoublestranded DNA antibodies. In both cases, no anticardiolipin antibodies were detected, and the results of cerebrospinal fluid analysis showed no infectious findings. In Case 1, anti-glutamate receptor e2 (GluRe2) antibody were detected in her serum and CSF. In Case 2, small focal lesions were revealed by brain MRI examination. Brain single photon emission computed tomography revealed diffuse brain hypoperfusion in both cases. The NP symptoms in the present cases improved after immunotherapy. Accordingly, these cases were diagnosed as NPSLE, and the combination of lymphopenia and NP symptoms was a clue for the early diagnosis and treatment of SLE. In young female patients with psychiatric symptoms, checking for blood cell differentiation could be a convenient method of screening for SLE. http://dx.doi.org/10.1016/j.npbr.2014.01.146
immune responses observed in autoimmune neuroinflammatory disease. Here, we identify a novel pathway for immune cell traffic from the brain that is associated with the rostral migratory stream, best known as a forebrain source of newly generated neurons. Targeted pharmacologic interruption of this immune cell traffic, with Fingolimod, influences anti-CNS T-cell responses in the cervical lymph nodes (CxLNs) and modulates the severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. This treatment also induced EAE in a disease-resistant transgenic (MOG-TCR) mouse strain, by altering dendritic cell-mediated T-regulatory lymphocyte function in the CxLNs, breaking CNS immune tolerance. These data represent the first description of an immune cell pathway, originating in the CNS, capable of dampening anti-CNS immune responses in the periphery. These data provide mechanistic insight into why Fingolimod treatment might, in some cases, exacerbate CNS neuroinflammation. They further suggest that focal therapeutic interventions may selectively modify anti-CNS immunity. http://dx.doi.org/10.1016/j.npbr.2014.01.144 Macrophage inhibitory cytokine-1 is associated with cognitive impairment and predicts cognitive decline – The Sydney Memory and Aging Study T. Fuchs a, J.N. Trollor a,b, J. Crawford b, B.T. Baune c, K. Samaras d,e, L. Campbell d,e, S.N. Breit f, H. Brodaty b,g, P. Sachdev b,h, E. Smith a,b, D.A. Brown f,* a
Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Sydney, NSW 2010, Australia b Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW 2010, Australia c Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia d Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia e Department of Endocrinology, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia f St Vincent's Centre for Applied Medical Research, St Vincent's Hospital and University of New South Wales, Sydney, NSW 2010, Australia g Dementia Collaborative Research Centre, School of Psychiatry, University of New South Wales, Sydney, Australia h Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, NSW, Australia *Corresponding author. Higher levels of macrophage inhibitory cytokine-1, also known as growth differentiation factor 15 (MIC-1/GDF15), are associated with inflammatory disease, adverse health outcomes and all-cause mortality. This study examined the relationships between MIC-1/GDF15 serum levels and global cognition, five cognitive domains, and mild cognitive impairment (MCI), at baseline (Wave 1) and prospectively at 2 years (Wave 2), in non-demented participants aged 70–90 years. Analyses were controlled for age, sex, education, Framingham risk score, history of cerebrovascular accident, acute myocardial infarction, angina, cancer, depression, C-reactive protein, tumor necrosis factor-a, interleukins 6 and 12, and apolipoprotein e4 genotype. Higher MIC-1/GDF15 levels were significantly associated with lower global cognition at both waves. Crosssectional associations were found between MIC-1/GDF15 and all cognitive domains in Wave 1 (all P < 0.001) and between processing speed, memory, and executive function in Wave 2 (all P < 0.001). Only a trend was found for the prospective
9
analyses, individuals with high MIC-1/GDF15 at baseline declined in global cognition, executive function, memory, and processing speed. However, when categorizing MIC-1/ GDF15 by tertiles, prospective analyses revealed statistically significant lower memory and executive function in Wave 2 in those in the upper tertile compared with the lower tertile. Receiver operating characteristics (ROC) analysis was used to determine MIC-1/GDF15 cutoff values associated with cognitive decline and showed that a MIC-1/GDF15 level exceeding 2764 pg/ml was associated with a 20% chance of decline from normal to MCI or dementia. In summary, MIC-1/GDF15 levels are associated with cognitive performance and cognitive decline. Further research is required to determine the pathophysiology of this relationship. http://dx.doi.org/10.1016/j.npbr.2014.01.145 Lymphopenia helps early diagnosis of systemic lupus erythematosus for patients with psychosis as an initial symptom Y. Chiba a,*, O. Katsuse a, H. Fujishiro a, A. Kamada a, T. Saito a, T. Ikura a, Y. Takahashi b, M. Kunii c, M. Takeno d, Y. Hirayasu a a
Department of Psychiatry, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan b Department of Pediatrics, Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama 886, Aoi-ku, Shizuoka 4208688, Japan c Department of Neurology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan d Department of Internal Medicine and Clinical Immunology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan *Corresponding author. Patients with systemic lupus erythematosus (SLE) frequently exhibit neuropsychiatric symptoms (neuropsychiatric SLE; NPSLE). Although some patients’ initial SLE symptoms are neuropsychiatric, it is difficult to diagnose them with SLE before the appearance of physical symptoms of SLE or relatively severe NP symptoms such as disturbance of consciousness or seizure. Hematological disorders are also frequent, even as the initial symptoms of SLE. Here we report two patients who presented with NP symptoms as initial symptoms of SLE, and lymphopenia was a useful symptom for the early diagnosis of SLE. Case 1 was a young woman with a past history of transient facial erythema. She suffered from psychosis, depression and mild cognitive impairment. Case 2 was a young woman who initially exhibited psychosis, mania and mild cognitive decline. Routine laboratory blood tests revealed lymphopenia, and additional blood tests revealed elevated antinuclear antibodies and antidoublestranded DNA antibodies. In both cases, no anticardiolipin antibodies were detected, and the results of cerebrospinal fluid analysis showed no infectious findings. In Case 1, anti-glutamate receptor e2 (GluRe2) antibody were detected in her serum and CSF. In Case 2, small focal lesions were revealed by brain MRI examination. Brain single photon emission computed tomography revealed diffuse brain hypoperfusion in both cases. The NP symptoms in the present cases improved after immunotherapy. Accordingly, these cases were diagnosed as NPSLE, and the combination of lymphopenia and NP symptoms was a clue for the early diagnosis and treatment of SLE. In young female patients with psychiatric symptoms, checking for blood cell differentiation could be a convenient method of screening for SLE. http://dx.doi.org/10.1016/j.npbr.2014.01.146