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Blood levels of histamine, interleukin-1β and tumor necrosis factor-α in Alzheimer's disease
FOURTH INTERNATIONAL
CONFERENCE
ON ALZHEIMER’S
381 INCREASED PROTEOLYTIC ACTIVITY IN ERYTHROCYTES
AND
LYMPHOCYTES FROM PATIENTS WITH ALZHEIMERS DISEASE.
J.-O. Karlsson, I. Janson, K. Blennow, I. Karlsson, B. Regland, A. Wallin and C.G. Gottfries. Department of Anatomy and Cell Biology and Department of Psychiatry and Neurochemistry, University of Giiteborg. S400 33 Goteborg, Sweden. Ca-independent and Ca-dependent proteolytic activity was significantly higher in etythrocytes from patients with Alzheimers disease compared to control subjects. Ca-dependent proteolytic activity was also higher in lymphocytes from patients with early Alzheimers disease (EAD). The level of calpastatin, an endogenous inhibitor of the proteolytic enzyme calpain. was lower in male patients with Alzheimers disease. Control male subjects had significantly higher level of calpastatin in the erythmcytes compared to female controls. Lymphocytes from patients with early Alzheimers disease had significantly lower levels of calpastatin compared to that of patients with late Alzheimers disease. The observed changes in the calpaimcalpastatin system of erythrocytes and lymphocytes may. be caused _ _ ._. by a general dysregulation of Ca homeostasis in cells of Alzheimer patients and may lead to calpain induced pathological changes and the appearance of NET.
382 THE
s93
DISEASE
Cytokines play an important role not only for initiation of immune reactivity but also for development of tissue injury. Among the many characteristics of Alzheimer’s disease is an upregulation of immune mediators in and around senile plaquesThis suggests that a sequence of immunological events is part of the pathology of AD. The hypothesis that amyloidogenesis results from an IL-I/IL-2 mediated acute phase reaction in the brain is now experimentally proved out. Ahhouth these brain cytokines levels are increased there are controversies as far as the serum and CSF concentrations. Serum levels of IL-I and IL-6 were determined in 25 patients with clinically diagnosed Alaheimer’s disease (AD), in 21 patients with vascular dementia(VD), in 16 patients with other dementias (OD) and 15 age and sex matched control subjects (Normal). The means and Standard Deviations for IL-1 I IL-2 respectively were: AD=13,41+9,03/ Il.36*20,9, VD= 13,4i4,74 19.21 *11,89, OD=l1.87*11,33, normal= 11,44*2,3/ 7,89i8,14. NINCDS -ADRDA and DSMIII-R criteria were used for the diagnosis of AD and Dementia respectively.Mean serum levels of IL-I and IL-2 did not differ signiticantly behveeen all groups. In the other hand there are controversies as far as serum and CSF immunoglobulins are concerned in dementias. We examined IGG, IGA and IGM by Nephelometry in serum of 43 patients with Alzheimer’s disease, 21 patients with vascular dementia, 11 patients with other dementias and 46 age-matched controls. The means and Standard Deviations were: AD: IGG=1085+391,7, IGA=228,6*121,7, IGM= 90,97+58,23. VD: IGG=1044,39*296, IGA=256,9*97,85. lGM=95,52 +30,41, OD: IGG=l338,6*576,5. IGA= 229,18+81,39, IGM=106,27*48,24, Normal: lGG=1270,061-294,2, lGA=259,6*117,9 and IGM= 119,56*54,3. There was a statistical serum IGG decrease in oatients with Alzheimer’s disease and vascular dementia (o=O.O02and p=O.Oil respectively) and IGM decrease in patients with Alzheimer’s disease (p=O.O06).Conclusively neither serum IL-1 and IL-2 nor IGG and IGA can be used for the difleerentialdiagnosis of dementias. Perhaps low IGM levels suggest Alzheimer’s disease rather than vascular dementia.
384
USE
OF
BOURU ALtTommoRous
I@
ON T CRLLS As
A
DIAGNOSTIC RARXER FOR ALZBXIMR’S DISEASE. S.H. Kell, R.M. Allman, L.E. Harrell, T. Liu, N. Solvason. Dapts. Medicine, Neurology, Microbiology, VA Med. Ctr., University of Alabama at Birmingham, 933 19th St S, Rm 219, Birmingham, AL 35294-2041. A new T cell phenotype was recently described resultino from the bindino of autochthonous IOM to the surf&e of peripheral-T lymphocytes. In a sample of 53 adults (mean age 73.2 + 9.1 years, 39 whites and 14 African Americans, 35 females, 24 patients with probable or possible Alzheimer's Disease), the number of IgM bound T cells per total T cells (%IgM+ T cells) was determined by staining peripheral blood lymphocytes for IgM and CD3. Double positive cells were indentified by FACS. A board certified neurologist with expertise in dementing illnesses (LU) and a geriatrician (SK), independently reviewed, without knowledge of the %IgM+ T cell results, the patient's cognitive history and medical evaluations to determine a cognitive diagnosis. The diagnosis of AD was based on NINCDS/ADRDA criteria. The mean %IgM T cells was 24.1 f 28.7%. There was a significant difference in the mean %IgM + T cells between Alsheimer's Disease (AD) and non-AD patients (35.6% f 30.2% and 14.6% f 23.9%, respectively, p < 0.001). When a cutoff of greater than 20% IgM+ T cells was utilized to predict the diagnosis of probable or possible AD, the sensitivity was 62.5% and the specificity was 89.7% (x2 = 15.9 and p < 0.001). The positive predictive value was 83.3% and the negative predictive value was 74.3%. This analysis revealed that only 3 non-AD patients had IgM+ T cell values greater than 20%. We conclude that in our patients with AD, a certain subset had greater than 20% of their T cells bound with IgM and that this test may serve as a supportive laboratory marker for the diagnosis of AD.
BLOOD LEVELS OF HISTAMINE, INTERLEUIUN-1B AND TUMOR NECROSIS FACTOR-a IN ALZHEIMER’S DISEASE. X.A. Alvarez, A. France-Maside, L. Fermindez-Novoa, J. Caamafio, M.J. G6mez, B. Novo, R. Zas and R. Cacabelos. Institute for CNS Disorders, Basic and Clinical Neurosciences Research Center, A CONha-Spain. Neuropathological changes occurring in Alzheimer’s disease (AD) are accompanied by a brain neuroimmune reaction. High levels of histamine (HA) and interletiin-18 (IL-IS) have been found in brain tissue, CSF and serum from AD patients, while tumor necrosis factor-o (TNF-IY) content tends to be markedly dished in serum and in most CNS regions in AD. In this study we have evaluated blood HA levels, serum concentrations of IL-18 and the plasma content of TNF-o in twenty patients with AD (age=66.6f6.45 years; range=57-78 years; 10 males/l0 females; 13 early-onset and 7 late-onset AD patients) and in age-matched control subjects (EC; N=20; age=65.55*5.86 years; range=55-78 years). Blood HA levels were higher in AD than in control subjects (AD=0.43f0.18 mnollml; EC=0.27*0.15 nmollml; p <0.05), and in early-onset AD than in late-onset AD patients (EOAD=0.53~0.18nmol/ml;LOAD=0.34fO.14nmol/ml,p<0.05). As compared with controls, the concentrations of IL-18 in serum were also increased in AD (AD=211.2*31.1 pg/ml; EC=183.4*24.4 pg/ml; p
383 385
IMMUNOLOGICAL ASPECTS OF DEMENTIASSERUM CYTOKINES AND IMMUNOGLOBULINES. M. Tsolaki, M. Kataropoulou , C.Tronzos , M.Sahsamanoglou G.Kyriagis , P.Grammaticos and A.Kuis
SERUM ,
u I-ANTICHYMOTRYPSIN
CONCENTRATIONS IN ALZHEIMER TYPEAND VASCULAR DEMENTIA
3rd Department of Neurology, Immunology Department, Aristotle University of Thessaloniki GH “G.Papanikolaou” and Department of Nuclear Medicine GH AHEPA Thessaloniki, Macedonia, Greece
Y. Yoshida.Y.0htani.T. Kawaguchi M.MurasakiandS.MRJRA
CONFERENCE
ON ALZHEIMER’S
381 INCREASED PROTEOLYTIC ACTIVITY IN ERYTHROCYTES
AND
LYMPHOCYTES FROM PATIENTS WITH ALZHEIMERS DISEASE.
J.-O. Karlsson, I. Janson, K. Blennow, I. Karlsson, B. Regland, A. Wallin and C.G. Gottfries. Department of Anatomy and Cell Biology and Department of Psychiatry and Neurochemistry, University of Giiteborg. S400 33 Goteborg, Sweden. Ca-independent and Ca-dependent proteolytic activity was significantly higher in etythrocytes from patients with Alzheimers disease compared to control subjects. Ca-dependent proteolytic activity was also higher in lymphocytes from patients with early Alzheimers disease (EAD). The level of calpastatin, an endogenous inhibitor of the proteolytic enzyme calpain. was lower in male patients with Alzheimers disease. Control male subjects had significantly higher level of calpastatin in the erythmcytes compared to female controls. Lymphocytes from patients with early Alzheimers disease had significantly lower levels of calpastatin compared to that of patients with late Alzheimers disease. The observed changes in the calpaimcalpastatin system of erythrocytes and lymphocytes may. be caused _ _ ._. by a general dysregulation of Ca homeostasis in cells of Alzheimer patients and may lead to calpain induced pathological changes and the appearance of NET.
382 THE
s93
DISEASE
Cytokines play an important role not only for initiation of immune reactivity but also for development of tissue injury. Among the many characteristics of Alzheimer’s disease is an upregulation of immune mediators in and around senile plaquesThis suggests that a sequence of immunological events is part of the pathology of AD. The hypothesis that amyloidogenesis results from an IL-I/IL-2 mediated acute phase reaction in the brain is now experimentally proved out. Ahhouth these brain cytokines levels are increased there are controversies as far as the serum and CSF concentrations. Serum levels of IL-I and IL-6 were determined in 25 patients with clinically diagnosed Alaheimer’s disease (AD), in 21 patients with vascular dementia(VD), in 16 patients with other dementias (OD) and 15 age and sex matched control subjects (Normal). The means and Standard Deviations for IL-1 I IL-2 respectively were: AD=13,41+9,03/ Il.36*20,9, VD= 13,4i4,74 19.21 *11,89, OD=l1.87*11,33, normal= 11,44*2,3/ 7,89i8,14. NINCDS -ADRDA and DSMIII-R criteria were used for the diagnosis of AD and Dementia respectively.Mean serum levels of IL-I and IL-2 did not differ signiticantly behveeen all groups. In the other hand there are controversies as far as serum and CSF immunoglobulins are concerned in dementias. We examined IGG, IGA and IGM by Nephelometry in serum of 43 patients with Alzheimer’s disease, 21 patients with vascular dementia, 11 patients with other dementias and 46 age-matched controls. The means and Standard Deviations were: AD: IGG=1085+391,7, IGA=228,6*121,7, IGM= 90,97+58,23. VD: IGG=1044,39*296, IGA=256,9*97,85. lGM=95,52 +30,41, OD: IGG=l338,6*576,5. IGA= 229,18+81,39, IGM=106,27*48,24, Normal: lGG=1270,061-294,2, lGA=259,6*117,9 and IGM= 119,56*54,3. There was a statistical serum IGG decrease in oatients with Alzheimer’s disease and vascular dementia (o=O.O02and p=O.Oil respectively) and IGM decrease in patients with Alzheimer’s disease (p=O.O06).Conclusively neither serum IL-1 and IL-2 nor IGG and IGA can be used for the difleerentialdiagnosis of dementias. Perhaps low IGM levels suggest Alzheimer’s disease rather than vascular dementia.
384
USE
OF
BOURU ALtTommoRous
I@
ON T CRLLS As
A
DIAGNOSTIC RARXER FOR ALZBXIMR’S DISEASE. S.H. Kell, R.M. Allman, L.E. Harrell, T. Liu, N. Solvason. Dapts. Medicine, Neurology, Microbiology, VA Med. Ctr., University of Alabama at Birmingham, 933 19th St S, Rm 219, Birmingham, AL 35294-2041. A new T cell phenotype was recently described resultino from the bindino of autochthonous IOM to the surf&e of peripheral-T lymphocytes. In a sample of 53 adults (mean age 73.2 + 9.1 years, 39 whites and 14 African Americans, 35 females, 24 patients with probable or possible Alzheimer's Disease), the number of IgM bound T cells per total T cells (%IgM+ T cells) was determined by staining peripheral blood lymphocytes for IgM and CD3. Double positive cells were indentified by FACS. A board certified neurologist with expertise in dementing illnesses (LU) and a geriatrician (SK), independently reviewed, without knowledge of the %IgM+ T cell results, the patient's cognitive history and medical evaluations to determine a cognitive diagnosis. The diagnosis of AD was based on NINCDS/ADRDA criteria. The mean %IgM T cells was 24.1 f 28.7%. There was a significant difference in the mean %IgM + T cells between Alsheimer's Disease (AD) and non-AD patients (35.6% f 30.2% and 14.6% f 23.9%, respectively, p < 0.001). When a cutoff of greater than 20% IgM+ T cells was utilized to predict the diagnosis of probable or possible AD, the sensitivity was 62.5% and the specificity was 89.7% (x2 = 15.9 and p < 0.001). The positive predictive value was 83.3% and the negative predictive value was 74.3%. This analysis revealed that only 3 non-AD patients had IgM+ T cell values greater than 20%. We conclude that in our patients with AD, a certain subset had greater than 20% of their T cells bound with IgM and that this test may serve as a supportive laboratory marker for the diagnosis of AD.
BLOOD LEVELS OF HISTAMINE, INTERLEUIUN-1B AND TUMOR NECROSIS FACTOR-a IN ALZHEIMER’S DISEASE. X.A. Alvarez, A. France-Maside, L. Fermindez-Novoa, J. Caamafio, M.J. G6mez, B. Novo, R. Zas and R. Cacabelos. Institute for CNS Disorders, Basic and Clinical Neurosciences Research Center, A CONha-Spain. Neuropathological changes occurring in Alzheimer’s disease (AD) are accompanied by a brain neuroimmune reaction. High levels of histamine (HA) and interletiin-18 (IL-IS) have been found in brain tissue, CSF and serum from AD patients, while tumor necrosis factor-o (TNF-IY) content tends to be markedly dished in serum and in most CNS regions in AD. In this study we have evaluated blood HA levels, serum concentrations of IL-18 and the plasma content of TNF-o in twenty patients with AD (age=66.6f6.45 years; range=57-78 years; 10 males/l0 females; 13 early-onset and 7 late-onset AD patients) and in age-matched control subjects (EC; N=20; age=65.55*5.86 years; range=55-78 years). Blood HA levels were higher in AD than in control subjects (AD=0.43f0.18 mnollml; EC=0.27*0.15 nmollml; p <0.05), and in early-onset AD than in late-onset AD patients (EOAD=0.53~0.18nmol/ml;LOAD=0.34fO.14nmol/ml,p<0.05). As compared with controls, the concentrations of IL-18 in serum were also increased in AD (AD=211.2*31.1 pg/ml; EC=183.4*24.4 pg/ml; p
383 385
IMMUNOLOGICAL ASPECTS OF DEMENTIASSERUM CYTOKINES AND IMMUNOGLOBULINES. M. Tsolaki, M. Kataropoulou , C.Tronzos , M.Sahsamanoglou G.Kyriagis , P.Grammaticos and A.Kuis
SERUM ,
u I-ANTICHYMOTRYPSIN
CONCENTRATIONS IN ALZHEIMER TYPEAND VASCULAR DEMENTIA
3rd Department of Neurology, Immunology Department, Aristotle University of Thessaloniki GH “G.Papanikolaou” and Department of Nuclear Medicine GH AHEPA Thessaloniki, Macedonia, Greece
Y. Yoshida.Y.0htani.T. Kawaguchi M.MurasakiandS.MRJRA