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Neuroinflammation Screening in Immunotherapy Trials against Alzheimer's Disease

Neuroinflammation Screening in Immunotherapy Trials against Alzheimer's Disease SAGE-Hindawi Access to Research International Journal of Alzheimer’s Disease Volume 2010, Article ID 638379, 3 pages doi:10.4061/2010/638379 Case Report Neuroinflammation Screening in Immunotherapy Trials against Alzheimer’s Disease 1 2 2 Niels Andreasen, Kaj Blennow, and Henrik Zetterberg Memory Clinic, M51, Department of Geriatric Medicine, Karolinska University Hospital, Huddinge, 17176 Stockholm, Sweden Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Mol ¨ ndal, Sweden Correspondence should be addressed to Henrik Zetterberg, henrik.zetterberg@gu.se Received 26 August 2010; Accepted 24 November 2010 Academic Editor: Akihiko Takashima Copyright © 2010 Niels Andreasen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Duetosideeffects in the form of meningoencephalitis in the interrupted phase II AN1792 trial of active antiamyloid β(Aβ) immunization against Alzheimer’s disease (AD), there has been concern that anti-Aβ immunization may cause destructive neuroinflammation. Here, we report on two patients fulfilling clinical AD criteria who were diagnosed with Lyme neuroborreliosis during screening before inclusion in anti-Aβ immunotherapy trials. The two cases illustrate the necessity of careful biochemical screening for neuroinflammatory/neuroinfectious conditions before an AD diagnosis is made and before clinical AD patients are included in trials of therapy that could impact the immune system. Should the two cases have been included and deteriorated, additional investigations might have led to the erroneous conclusion that therapy-induced meningoencephalitis had occurred. 1. Introduction elevated ratio of albumin concentrations in cerebrospinal fluid (CSF) and serum/plasma, CSF monocytosis and IgG Clinical trials of disease-modifying treatments for AD have and IgM bands selectively in CSF [3, 4]. These changes are been struck by adverse events involving the immune sys- also seen in therapy-induced meningoencephalitis [1]. We tem. In the clinical trial of the active antiamyloid β(Aβ) here present two clinical AD cases who were diagnosed with vaccine AN1792, a small but notable number of patients Lyme neuroborreliosis (LNB) during screening for eligibility developed meningoencephalitis [1], and treatment with the to enter an anti-Aβ immunotherapy trial. Should the two passive anti-Aβ immunotherapy AAB001 led to vasogenic cases have been included and deteriorated, additional edema in some individuals [2]. The Aβ immunogens that investigations might have led to the erroneous conclusion are now being used in the second generation of active that therapy-induced meningoencephalitis had occurred. immunization trials have been modified to reduce the risk of meningoencephalitis. However, academia, industry, and 2. Case Descriptions regulators are on their toes to identify immunological side effects as early as possible to avoid patient injury. Therefore, it NO is a 70-year-old retired man. His health history is is of utmost importance to identify and exclude patients who remarkable for a cholecystectomy in 2001 that was followed fulfill clinical AD criteria but who already before the start of by confusion. An epileptic seizure was suspected and the therapy show biochemical signs of neuroinflammation. patient was treated with carbamazepine for a short period. A number of standard laboratory tests are useful for He did not have any new seizures after carbamazepine was this purpose. Typical laboratory findings in patients with withdrawn. The patient has a positive family history of AD neuroinflammatory/neuroinfectious conditions include im- with both his grandfather and mother having been diagnosed paired blood-brain barrier function, as reflected by an with the disease. 2 International Journal of Alzheimer’s Disease Table 1: Biochemical findings in the cerebrospinal fluid of two patients with cognitive problems and Lyme neuroborreliosis. Albumin ratio IgM-index CSF monocytes Serum anti-Borrelia CSF anti-Borrelia Case IgG-index (<0.63) (<10.2) (<0.060) (<5/μL) antibodies antibodies Man, 70 years 13.5 0.49 0.28 108 Negative Positive Woman, 68 years 33.4 1.82 0.93 84 Negative Positive Values in parentheses show laboratory reference limits. In 1995, NO started to complain of cognitive decline that progressive cognitive deterioration, and in February 2006 she progressed over the years with aphasia, apraxia, and agnosia. fulfilled clinical criteria for AD and started treatment with He developed spatial deficits with orientation difficulties and galantamine. The diagnosis was based on the anamnestic a strong tendency to misplace belongings. In 2002, he was record and supported by findings on MRI and SPECT, as diagnosed with AD. A magnetic resonance imaging (MRI) well as neuropsychological test results. To further secure scan of the brain was normal with no atrophy or white matter her diagnosis, a CSF tap was planned but she declined this changes. EEG showed slow postcentral rhythm (7 Hz), and investigation. The patient wasterrifiedof her diagnosisand single positron emission computed tomography (SPECT) of wanted to fight it the best she could. She had heard of ongo- the brain revealed frontotemporal hypoperfusion with left- ing immunization trials at the Karolinska University Hospital side predominance. CSF analyses showed slightly elevated and was referred for being evaluated for eligibility. As a part albumin ratio of 12 (<10) as a sign of mildly impaired blood- of this evaluation, a baseline CSF tap was mandatory and she brain barrier function, normal cell counts, elevated total-tau agreed on this. The results showed completely normal T-tau, (T-tau) of 589 ng/L (laboratory reference limit <400 ng/L), P-tau ,and Aβ1-42 concentrations in CSF speaking against and normal Aβ1-42 concentration 495 ng/L (>450). He AD. However, the albumin ratio was strongly elevated, CSF was heterozygous for the Alzheimer-associated ε4 allele of monocyte counts high, and both the IgG- and IgM-indices the apolipoprotein E gene. Neurological examination was elevated (Table 1) with oligoclonal IgG and IgM bands normal, and the neuropsychological profile and clinical selectively in CSF as a further sign of intrathecal IgG and IgM evaluation were consistent with AD. The patient started production. The anti-Borrelia titer in serum was negative but treatment with galantamine. His cognition improved with positive in CSF. She was treated with standard doxycycline the minimental state examination (MMSE) score rising from 200 mg twice a day for 10 days. She was then followed 22 to 28 points. with repeated CSF taps for 1.5 year showing normalization In November 2006, the patient was screened for a clinical of the blood-brain barrier function and cell counts. Her trial of active immunization against Aβ. His cognition had cognitive status slowly improved during this period and the been rather stable over the four years on treatment with only AD diagnosis was disposed. a minor decrease of the MMSE score from 28 to 25. He had no somatic complaints and his somatic status was normal. He showed no symptoms of infection and had no neurological 3. Discussion complaints. An MRI scan of the brain showed slight atrophy with mild white matter changes consistent with AD. The two cases illustrate the necessity of identifying treatable A lumbar puncture was performed at baseline before causes of memory problems. The case histories are of inclusion in the trial, and the biomarkers for AD, T-tau, relevance both to clinicians who evaluate and treat patients phospho-tau (P-tau ), and Aβ1-42 were 520 (<400), 96 181 181 with cognitive problems and also to the pharmaceutical (<80), and 460 (>450) ng/L, respectively, which is consistent industry that designs trials of drug candidates that might with AD. The albumin ratio was further elevated, and, impact the immune system. For one of the two cases, BS, surprisingly, CSF monocyte counts were high and so was the the spinal tap was essential with the CSF test results radically IgM-index (Table 1). Agarose gel electrophoresis of serum changing the diagnosis from an incurable, ultimately fatal and CSF followed by immunoblotting against IgM supported disease to a treatable spirochetal infection. NO suffers from ongoing intrathecal IgM production. This neurochemical AD but during the disease process he contracted LNB that picture is consistent with neuroinflammation. Anti-Borrelia could have been mistaken for a side effect of the anti-Aβ titers were positive in CSF but negative in serum. The patient immunization should he have been included in the trial. was treated with standard doxycycline 200 mg twice a day LNB is a multisystem disease caused by infection with for 10 days. He was then followed with repeated CSF taps the spirochete Borrelia burgdorferi and the most common for 1.5 year during which his albumin ratio and cell counts infectious cause of chronic neuroinflammation. Neurologic were normalized. However, T-tau and P-tau181 remained complications of LNB include encephalitis, meningitis, and pathologically elevated and Aβ1-42 turned low indicating an dementia, as well as a broad range of peripheral neuropathies ongoing AD process. Accordingly, the patient has continued [5]. The many symptoms of LNB may mimic neurodegener- to deteriorate cognitively during the followup period. ative diseases, such as AD and amyotrophic lateral sclerosis The next case, BS, is a 68-year-old woman. She is occu- (ALS). Although there is no strong evidence that these pied as a hairdresser, still working part-time. Her health diseases are caused by spirochetal infections, diagnosis of history is unremarkable. In 2003, she started to suffer from each must rule out the possibility of LNB. International Journal of Alzheimer’s Disease 3 To the best of our knowledge, there are no published Alzheimer Disease and Associated Disorders,vol. 22, no. 3,p. 308, 2008. studies on the prevalence of LNB in patients attending a memory clinic. At least four studies have examined the [7] M. Gutacker, C. Valsangiacomo, T. Balmelli, M. V. Bernasconi, C. Bouras, and J. C. Piffaretti, “Arguments against the prevalence of anti-Borrelia burgdorferi antibodies in serum involvement of Borrelia burgdorferi sensu lato in Alzheimer’s in AD cases and controls without finding evidence of disease,” Research in Microbiology, vol. 149, no. 1, pp. 31–37, an association with AD [6–9]. Two cases of LNB were diagnosed in 1,089 consecutive patients (aged 23–89 years) [8] A. R. Marques,S.C.Weir, G. A. Fahle, and S. H. Fischer, “Lack who underwent lumbar puncture as a part of the routine of evidence of Borrelia involvement in Alzheimer’s disease,” diagnostic evaluation between February 2001 and March Journal of Infectious Diseases, vol. 182, no. 3, pp. 1006–1007, 2007 at the specialized memory clinic in Malmo[ ¨ 10], but it should be noted that these patients were selected referral [9] R. McLaughlin, N. M. K. Ng Ying Kin, M. F. Chen, N. P. patients. The prevalence of intrathecal immunoglobulin V. Nair, and E. C. S. Chan, “Alzheimer’s disease may not be production in AD patients ranges from 5 to 20% in different aspirochetosis,” NeuroReport, vol. 10, no. 7, pp. 1489–1491, studies [11–13]. In conclusion, analysis of CSF taken from patients [10] H. Zetterberg, K. Tullhog ¨ , O. Hansson, L. Minthon, E. Londos, at baseline, before treatment, could be useful in clinical and K. Blennow, “Low incidence of post-lumbar puncture trials for identifying and excluding individuals with chronic headache in 1,089 consecutive memory clinic patients,” Euro- infectious or inflammatory CNS disorders that can mimic or pean Neurology, vol. 63, no. 6, pp. 326–330, 2010. aggravate the symptoms of AD. The inclusion of such cases [11] K. Blennow, A. Wallin, P. Davidsson, P. Fredman, C. G. in trials could result in the wrong conclusion that an adverse Gottfries, and L. Svennerholm, “Intra-blood-brain-barrier effect, such as encephalitis, was related to the drug being synthesis of immunoglobulins in patients with dementia of the Alzheimer type,” Alzheimer Disease and Associated Disorders, tested. Baseline CSF samples can also be used in comparisons vol. 4, no. 2, pp. 79–86, 1990. with CSF collected after treatment initiation. The benefit [12] K. Blennow, A. Wallin, P. Fredman, C. G. Gottfries, I. Karlsson, of such comparisons is that even minor inflammatory and L. Svennerholm, “Intrathecal synthesis of immunoglobu- activation within the CNS, as a result of adverse effects of lins in patients with Alzheimer’s disease,” European Neuropsy- thedrug, can beidentified. Thus, CSFbiomarkers could chopharmacology, vol. 1, no. 1, pp. 79–81, 1990. allow safety monitoring during clinical trials. Longitudinal [13] R. Zimmermann, G. Beck, S. Knispel et al., “Intrathecal IgG CSF sampling during the treatment period might indicate synthesis in patients with alterations in the neurochemical whether a certain drug induces harmful immune activation dementia diagnostics,” Journal of Alzheimer’s Disease, vol. 19, over the long term. no. 4, pp. 1199–1203, 2010. Considering CSF analyses in a broader perspective, we [14] K. Blennow, A. Wallin, and O. Hager, “Low frequency of thinkaspinal tapshouldbeconsideredin every patient post-lumbar puncture headache in demented patients,” Acta who seeks medical advice for cognitive problems, at least in Neurologica Scandinavica, vol. 88, no. 3, pp. 221–223, 1993. areas where LNB is endemic and in particular if the clinical [15] E. R. Peskind, R. Riekse, J. F. Quinn et al., “Safety and presentation is atypical. The safety and acceptability of the acceptability of the research lumbar puncture,” Alzheimer procedure support this view [10, 14, 15]. Disease and Associated Disorders, vol. 19, no. 4, pp. 220–225, References [1] J. M. Orgogozo, S. Gilman, J. F. Dartigues et al., “Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization,” Neurology, vol. 61, no. 1, pp. 46–54, [2] S. Salloway, R. Sperling, S. Gilman et al., “A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease,” Neurology, vol. 73, no. 24, pp. 2061–2070, [3] G. Tibbling, H. Link, and S. Ohman, “Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values,” Scandinavian Journal of Clinical and Laboratory Investigation, vol. 37, no. 5, pp. 385–390, 1977. [4] C. A. Vedeler and A. Storstein, “Autoimmune limbic encephalitis,” Acta Neurologica Scandinavica Supplementum, no. 189, pp. 63–67, 2009. [5] A.R.Pachner and I.Steiner,“Lyme neuroborreliosis: infec- tion, immunity, and inflammation,” Lancet Neurology,vol. 6, no. 6, pp. 544–552, 2007. [6] A. Galbussera, L. Tremolizzo, V. Isella et al., “Lack of evidence for borrelia burgdorferi seropositivity in Alzheimer disease,” MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Alzheimer's Disease Hindawi Publishing Corporation

Neuroinflammation Screening in Immunotherapy Trials against Alzheimer's Disease

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Hindawi Publishing Corporation
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Copyright © 2010 Niels Andreasen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

SAGE-Hindawi Access to Research International Journal of Alzheimer’s Disease Volume 2010, Article ID 638379, 3 pages doi:10.4061/2010/638379 Case Report Neuroinflammation Screening in Immunotherapy Trials against Alzheimer’s Disease 1 2 2 Niels Andreasen, Kaj Blennow, and Henrik Zetterberg Memory Clinic, M51, Department of Geriatric Medicine, Karolinska University Hospital, Huddinge, 17176 Stockholm, Sweden Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Mol ¨ ndal, Sweden Correspondence should be addressed to Henrik Zetterberg, henrik.zetterberg@gu.se Received 26 August 2010; Accepted 24 November 2010 Academic Editor: Akihiko Takashima Copyright © 2010 Niels Andreasen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Duetosideeffects in the form of meningoencephalitis in the interrupted phase II AN1792 trial of active antiamyloid β(Aβ) immunization against Alzheimer’s disease (AD), there has been concern that anti-Aβ immunization may cause destructive neuroinflammation. Here, we report on two patients fulfilling clinical AD criteria who were diagnosed with Lyme neuroborreliosis during screening before inclusion in anti-Aβ immunotherapy trials. The two cases illustrate the necessity of careful biochemical screening for neuroinflammatory/neuroinfectious conditions before an AD diagnosis is made and before clinical AD patients are included in trials of therapy that could impact the immune system. Should the two cases have been included and deteriorated, additional investigations might have led to the erroneous conclusion that therapy-induced meningoencephalitis had occurred. 1. Introduction elevated ratio of albumin concentrations in cerebrospinal fluid (CSF) and serum/plasma, CSF monocytosis and IgG Clinical trials of disease-modifying treatments for AD have and IgM bands selectively in CSF [3, 4]. These changes are been struck by adverse events involving the immune sys- also seen in therapy-induced meningoencephalitis [1]. We tem. In the clinical trial of the active antiamyloid β(Aβ) here present two clinical AD cases who were diagnosed with vaccine AN1792, a small but notable number of patients Lyme neuroborreliosis (LNB) during screening for eligibility developed meningoencephalitis [1], and treatment with the to enter an anti-Aβ immunotherapy trial. Should the two passive anti-Aβ immunotherapy AAB001 led to vasogenic cases have been included and deteriorated, additional edema in some individuals [2]. The Aβ immunogens that investigations might have led to the erroneous conclusion are now being used in the second generation of active that therapy-induced meningoencephalitis had occurred. immunization trials have been modified to reduce the risk of meningoencephalitis. However, academia, industry, and 2. Case Descriptions regulators are on their toes to identify immunological side effects as early as possible to avoid patient injury. Therefore, it NO is a 70-year-old retired man. His health history is is of utmost importance to identify and exclude patients who remarkable for a cholecystectomy in 2001 that was followed fulfill clinical AD criteria but who already before the start of by confusion. An epileptic seizure was suspected and the therapy show biochemical signs of neuroinflammation. patient was treated with carbamazepine for a short period. A number of standard laboratory tests are useful for He did not have any new seizures after carbamazepine was this purpose. Typical laboratory findings in patients with withdrawn. The patient has a positive family history of AD neuroinflammatory/neuroinfectious conditions include im- with both his grandfather and mother having been diagnosed paired blood-brain barrier function, as reflected by an with the disease. 2 International Journal of Alzheimer’s Disease Table 1: Biochemical findings in the cerebrospinal fluid of two patients with cognitive problems and Lyme neuroborreliosis. Albumin ratio IgM-index CSF monocytes Serum anti-Borrelia CSF anti-Borrelia Case IgG-index (<0.63) (<10.2) (<0.060) (<5/μL) antibodies antibodies Man, 70 years 13.5 0.49 0.28 108 Negative Positive Woman, 68 years 33.4 1.82 0.93 84 Negative Positive Values in parentheses show laboratory reference limits. In 1995, NO started to complain of cognitive decline that progressive cognitive deterioration, and in February 2006 she progressed over the years with aphasia, apraxia, and agnosia. fulfilled clinical criteria for AD and started treatment with He developed spatial deficits with orientation difficulties and galantamine. The diagnosis was based on the anamnestic a strong tendency to misplace belongings. In 2002, he was record and supported by findings on MRI and SPECT, as diagnosed with AD. A magnetic resonance imaging (MRI) well as neuropsychological test results. To further secure scan of the brain was normal with no atrophy or white matter her diagnosis, a CSF tap was planned but she declined this changes. EEG showed slow postcentral rhythm (7 Hz), and investigation. The patient wasterrifiedof her diagnosisand single positron emission computed tomography (SPECT) of wanted to fight it the best she could. She had heard of ongo- the brain revealed frontotemporal hypoperfusion with left- ing immunization trials at the Karolinska University Hospital side predominance. CSF analyses showed slightly elevated and was referred for being evaluated for eligibility. As a part albumin ratio of 12 (<10) as a sign of mildly impaired blood- of this evaluation, a baseline CSF tap was mandatory and she brain barrier function, normal cell counts, elevated total-tau agreed on this. The results showed completely normal T-tau, (T-tau) of 589 ng/L (laboratory reference limit <400 ng/L), P-tau ,and Aβ1-42 concentrations in CSF speaking against and normal Aβ1-42 concentration 495 ng/L (>450). He AD. However, the albumin ratio was strongly elevated, CSF was heterozygous for the Alzheimer-associated ε4 allele of monocyte counts high, and both the IgG- and IgM-indices the apolipoprotein E gene. Neurological examination was elevated (Table 1) with oligoclonal IgG and IgM bands normal, and the neuropsychological profile and clinical selectively in CSF as a further sign of intrathecal IgG and IgM evaluation were consistent with AD. The patient started production. The anti-Borrelia titer in serum was negative but treatment with galantamine. His cognition improved with positive in CSF. She was treated with standard doxycycline the minimental state examination (MMSE) score rising from 200 mg twice a day for 10 days. She was then followed 22 to 28 points. with repeated CSF taps for 1.5 year showing normalization In November 2006, the patient was screened for a clinical of the blood-brain barrier function and cell counts. Her trial of active immunization against Aβ. His cognition had cognitive status slowly improved during this period and the been rather stable over the four years on treatment with only AD diagnosis was disposed. a minor decrease of the MMSE score from 28 to 25. He had no somatic complaints and his somatic status was normal. He showed no symptoms of infection and had no neurological 3. Discussion complaints. An MRI scan of the brain showed slight atrophy with mild white matter changes consistent with AD. The two cases illustrate the necessity of identifying treatable A lumbar puncture was performed at baseline before causes of memory problems. The case histories are of inclusion in the trial, and the biomarkers for AD, T-tau, relevance both to clinicians who evaluate and treat patients phospho-tau (P-tau ), and Aβ1-42 were 520 (<400), 96 181 181 with cognitive problems and also to the pharmaceutical (<80), and 460 (>450) ng/L, respectively, which is consistent industry that designs trials of drug candidates that might with AD. The albumin ratio was further elevated, and, impact the immune system. For one of the two cases, BS, surprisingly, CSF monocyte counts were high and so was the the spinal tap was essential with the CSF test results radically IgM-index (Table 1). Agarose gel electrophoresis of serum changing the diagnosis from an incurable, ultimately fatal and CSF followed by immunoblotting against IgM supported disease to a treatable spirochetal infection. NO suffers from ongoing intrathecal IgM production. This neurochemical AD but during the disease process he contracted LNB that picture is consistent with neuroinflammation. Anti-Borrelia could have been mistaken for a side effect of the anti-Aβ titers were positive in CSF but negative in serum. The patient immunization should he have been included in the trial. was treated with standard doxycycline 200 mg twice a day LNB is a multisystem disease caused by infection with for 10 days. He was then followed with repeated CSF taps the spirochete Borrelia burgdorferi and the most common for 1.5 year during which his albumin ratio and cell counts infectious cause of chronic neuroinflammation. Neurologic were normalized. However, T-tau and P-tau181 remained complications of LNB include encephalitis, meningitis, and pathologically elevated and Aβ1-42 turned low indicating an dementia, as well as a broad range of peripheral neuropathies ongoing AD process. Accordingly, the patient has continued [5]. The many symptoms of LNB may mimic neurodegener- to deteriorate cognitively during the followup period. ative diseases, such as AD and amyotrophic lateral sclerosis The next case, BS, is a 68-year-old woman. She is occu- (ALS). Although there is no strong evidence that these pied as a hairdresser, still working part-time. Her health diseases are caused by spirochetal infections, diagnosis of history is unremarkable. In 2003, she started to suffer from each must rule out the possibility of LNB. International Journal of Alzheimer’s Disease 3 To the best of our knowledge, there are no published Alzheimer Disease and Associated Disorders,vol. 22, no. 3,p. 308, 2008. studies on the prevalence of LNB in patients attending a memory clinic. At least four studies have examined the [7] M. Gutacker, C. Valsangiacomo, T. Balmelli, M. V. Bernasconi, C. Bouras, and J. C. Piffaretti, “Arguments against the prevalence of anti-Borrelia burgdorferi antibodies in serum involvement of Borrelia burgdorferi sensu lato in Alzheimer’s in AD cases and controls without finding evidence of disease,” Research in Microbiology, vol. 149, no. 1, pp. 31–37, an association with AD [6–9]. Two cases of LNB were diagnosed in 1,089 consecutive patients (aged 23–89 years) [8] A. R. Marques,S.C.Weir, G. A. Fahle, and S. H. Fischer, “Lack who underwent lumbar puncture as a part of the routine of evidence of Borrelia involvement in Alzheimer’s disease,” diagnostic evaluation between February 2001 and March Journal of Infectious Diseases, vol. 182, no. 3, pp. 1006–1007, 2007 at the specialized memory clinic in Malmo[ ¨ 10], but it should be noted that these patients were selected referral [9] R. McLaughlin, N. M. K. Ng Ying Kin, M. F. Chen, N. P. patients. The prevalence of intrathecal immunoglobulin V. Nair, and E. C. S. Chan, “Alzheimer’s disease may not be production in AD patients ranges from 5 to 20% in different aspirochetosis,” NeuroReport, vol. 10, no. 7, pp. 1489–1491, studies [11–13]. In conclusion, analysis of CSF taken from patients [10] H. Zetterberg, K. Tullhog ¨ , O. Hansson, L. Minthon, E. Londos, at baseline, before treatment, could be useful in clinical and K. Blennow, “Low incidence of post-lumbar puncture trials for identifying and excluding individuals with chronic headache in 1,089 consecutive memory clinic patients,” Euro- infectious or inflammatory CNS disorders that can mimic or pean Neurology, vol. 63, no. 6, pp. 326–330, 2010. aggravate the symptoms of AD. The inclusion of such cases [11] K. Blennow, A. Wallin, P. Davidsson, P. Fredman, C. G. in trials could result in the wrong conclusion that an adverse Gottfries, and L. Svennerholm, “Intra-blood-brain-barrier effect, such as encephalitis, was related to the drug being synthesis of immunoglobulins in patients with dementia of the Alzheimer type,” Alzheimer Disease and Associated Disorders, tested. Baseline CSF samples can also be used in comparisons vol. 4, no. 2, pp. 79–86, 1990. with CSF collected after treatment initiation. The benefit [12] K. Blennow, A. Wallin, P. Fredman, C. G. Gottfries, I. Karlsson, of such comparisons is that even minor inflammatory and L. Svennerholm, “Intrathecal synthesis of immunoglobu- activation within the CNS, as a result of adverse effects of lins in patients with Alzheimer’s disease,” European Neuropsy- thedrug, can beidentified. Thus, CSFbiomarkers could chopharmacology, vol. 1, no. 1, pp. 79–81, 1990. allow safety monitoring during clinical trials. Longitudinal [13] R. Zimmermann, G. Beck, S. Knispel et al., “Intrathecal IgG CSF sampling during the treatment period might indicate synthesis in patients with alterations in the neurochemical whether a certain drug induces harmful immune activation dementia diagnostics,” Journal of Alzheimer’s Disease, vol. 19, over the long term. no. 4, pp. 1199–1203, 2010. Considering CSF analyses in a broader perspective, we [14] K. Blennow, A. Wallin, and O. Hager, “Low frequency of thinkaspinal tapshouldbeconsideredin every patient post-lumbar puncture headache in demented patients,” Acta who seeks medical advice for cognitive problems, at least in Neurologica Scandinavica, vol. 88, no. 3, pp. 221–223, 1993. areas where LNB is endemic and in particular if the clinical [15] E. R. Peskind, R. Riekse, J. F. Quinn et al., “Safety and presentation is atypical. The safety and acceptability of the acceptability of the research lumbar puncture,” Alzheimer procedure support this view [10, 14, 15]. Disease and Associated Disorders, vol. 19, no. 4, pp. 220–225, References [1] J. M. Orgogozo, S. Gilman, J. F. Dartigues et al., “Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization,” Neurology, vol. 61, no. 1, pp. 46–54, [2] S. Salloway, R. Sperling, S. Gilman et al., “A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease,” Neurology, vol. 73, no. 24, pp. 2061–2070, [3] G. Tibbling, H. Link, and S. Ohman, “Principles of albumin and IgG analyses in neurological disorders. I. Establishment of reference values,” Scandinavian Journal of Clinical and Laboratory Investigation, vol. 37, no. 5, pp. 385–390, 1977. [4] C. A. Vedeler and A. Storstein, “Autoimmune limbic encephalitis,” Acta Neurologica Scandinavica Supplementum, no. 189, pp. 63–67, 2009. [5] A.R.Pachner and I.Steiner,“Lyme neuroborreliosis: infec- tion, immunity, and inflammation,” Lancet Neurology,vol. 6, no. 6, pp. 544–552, 2007. [6] A. Galbussera, L. Tremolizzo, V. Isella et al., “Lack of evidence for borrelia burgdorferi seropositivity in Alzheimer disease,” MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

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International Journal of Alzheimer's Disease – Hindawi Publishing Corporation

Published: Dec 19, 2010

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