HIVERA JTC 2011-Full-proposal application form

HIVERA Call for Proposals 2011 for "European Research Projects on AIDS / HIV"

Full-proposal application form

All fields must be completed using "Arial font, size 11" characters. Please note that incomplete full-proposals, proposals using a different format or exceeding length limitations of any sections will be rejected without further review.

Project title
Multidisciplinary Survey of elderly HIV infected persons in Germany and Turkey

Acronym (max. 10 characters) Project duration Total requested funding

cognition
60 months

Keywords (Identify between three and seven keywords that represent the scientific content
Aging, cerebrovascular disease, metabolic disease, comorbidities, osteoporosis, HIVassociated neurocognitive disorder, neurodegeneration

Project abstract (max. page)

HIV-related immunological and multisystem accelerated aging contributes to the premature occurrence of age-related comorbidities such as cardiovascular disease, dyslipidemia, osteoporosis, frailty and cognitive decline (Goulet, Fultz et al. 2007). The immune dysregulation, can hasten cardiovascular, cerebrovascular and bone disease and precede their overt manifestation by years. Frailty, a clinical syndrome characterized by multisystem dysregulation and increased vulnerability to stressors, occurs prematurely in HIV-infected persons especially those with advanced disease (Onen and Overton 2011). The aging HIV population is at increased risk for cognitive decline. However, whether this dysfunction reflects accelerated neuropathological processes associated with HIV associated neurocognitive disorders (HAND) or with other neurodegenerative diseases such as Alzheimers disease or Parkinsons disease remains to be determined. The project aims to setup a multidisciplinary survey of elderly HIV infected persons to assess different aspects of aging HIV individuals.

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Signature of coordinator

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Project coordinator (= partner 1)

Last Name First Name Institution Department Address Post code City Country Phone Fax E-mail Other personnel participating in the project (please provide last and first names and positions, 1 line per person)

Endres Anne-Sophie Universittsmedizin Charit, Forschungsgruppe Geriatrie Geriatrie Reinickendorferstr. 61 13347 Berlin Germany 0049 30 45472121 0049 30 45941992 anne-sophie.endres@egzb.de Lindenberger, Ulman, data management MPI f. Bildungsforschung Pawalec, Graham, Immunology , Universittsklinikum Tbingen Steinhagen-Thieen, Geriatrie, Lipidambulanz Charit Bertram, Lars, Max Planck Institute for Molecular Genetics

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Partner 2

Last Name First Name Institution Department Address Post code City Country Phone Fax E-mail Other personnel participating in the project (please provide last and first names and positions, 1 line per person)

Arendt Gabriele Heinrich-Heine Universitt Department of Neurology, Medical Faculty Moorenstrasse 5 40225 Dsseldorf Germany +49 211-81-18981 +49 211-81-04903 Gabriele.Arendt@uni-duesseldorf.de

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Partner 3

Last Name First Name Institution Department Address Post code City Country Phone Fax E-mail Other personnel participating in the project (please provide last and first names and positions, 1 line per person)

Cinque Paola San Raffaele Hospital Division of Infectious Diseases Via Stamira d'Ancona 20 20127 Milan Italy +39-02-26437985 +39-02-26437989 cinque.paola@hsr.it .

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Partner 4
Last Name First Name Institution Department Address Post code City Country Phone Fax E-mail Other personnel participating in the project (please provide last and first names and positions, 1 line per person) Hahn Katrin Universittsmedizin Charit Department of Neurology Charitplatz 1 10117 Berlin Germany +49 30 450 660049 +49 30 450 560932 katrin.hahn@charite.de Fiebach, Jochen Schreiber, Stephan

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Partner 5

Last Name First Name Institution Department Address Post code City Country Phone Fax E-mail Other personnel participating in the project (please provide last and first names and positions, 1 line per person)

Yaman Hakan Akdeniz University Faculty of Medicine (AUFOM) General Medicine Dumlupnar Bulvar 07070 Kamps-Antalya Antalya Turkey 0(242) 249 60 00/ 6860 0(242) 249 68 61 hakanyaman@akdeniz.edu.tr

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Partner 6

Last Name First Name Institution Department Address Post code City Country Phone Fax E-mail Other personnel participating in the project (please provide last and first names and positions, 1 line per person)

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Project description
1. Background and present state of the art in the research field (max. 2 pages)
Neurological complications associated with aging There is a relatively vivid scientific discussion whether there is a higher prevalence of HIVassociated dementia in HIV-positive individuals > 50 years. There is only one group (Valcour, Shikuma et al. 2004) proving this in a well-designed study, but others couldnt confirm Victor Valcours results (Joska, Gouse et al. 2010). Thus, age might or might not be a risk factor for HIV-associated neurological disease (HAND). Identifying risk factors for developing dementia is crucial given the persistently high prevalence of HAND in the era of combination antiretroviral therapy (cART). The term HIV-associated neurocognitive disorders (HAND), represents a group of syndromes of varying degrees of cognitive impairment and associated functioning in HIVinfected individuals including asymptomatic neuropsychological impairment (ANI), HIVassociated mild neurocognitive disorder (MND), and HIV-associated dementia (HAD) (Antinori, Arendt et al. 2007). However the aging HIV population is also at increased risk for CNS diseases associated with aging such as cognitive decline, which can be associated with Alzheimers disease and Parkinsons disease like pathology (Deeks 2009; Xu and Ikezu 2009). Older adults (>50yrs) seem to be at higher risk for neurocognitive dysfunction because of age-related brain vulnerability. However, whether this dysfunction reflects accelerated neuropathological processes associated with HAND or with other neurodegenerative diseases such as Alzheimers disease or Parkinsons disease remains to be determined. Alzheimers or Parkinsons disease-like pathological changes observed in HIV infected antiretrovirally treated patients include elevated levels of hyperphosphorylated Tau (p-Tau) in the hippocampus and beta-amyloid deposition in the frontal cortex and hippocampus (Brew, Pemberton et al. 2005; Green, Masliah et al. 2005; Anthony, Ramage et al. 2006; Achim, Adame et al. 2009). Tisch et al. described increased levels of alpha-synuclein (Syn) in the substantia nigra associated with an increased risk for Parkinsons disease in aging HIV positive patients on antiretroviral therapy (Tisch and Brew 2009). Alpha-synuclein as a hallmark in Parkinson disease (PD) and other synucleinopathies is distributed throughout the nervous system, including the central nervous system (CNS), sympathetic ganglia, enteric nervous system, cardiac and pelvic plexus, submandibular gland, adrenal medulla and skin (Jellinger 2011; Wakabayashi, Mori et al. 2011). The neuropathogenesis of HAND is considered to be initiated by HIV infection, replication within the brain parenchyma and secondary neuroinflammation and immune activation of resident glia and tertiary neuronal injury (Nolting, Lindecke et al. 2009; Gannon, Khan et al. 2011; McArthur, Steiner et al. 2011).Cerebrospinal fluid (CSF) markers of immunactivation

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and inflammation are commonly detected in patients with HAND including in individuals with long duration aviremia, suggesting sustained CNS macrophage activation (McArthur, Steiner et al. 2011). Several publications have suggested that HAND prevalence varies among populations based upon clade predominance , representing and independent risk factor for HAND (Yepthomi, Paul et al. 2006; Rao, Sas et al. 2008)There are common traits in the pathogenesis of HAND and neurodegenerative diseases such as inflammation like activated microglia (Minagar, Shapshak et al. 2002; Ting, Brew et al. 2007), cytokine products in CSF and serum (Town, Laouar et al. 2008; Brew, Crowe et al. 2009; Sokolova, Hill et al. 2009) as well as cellular degrading pathways as well as oxidative stress (Brew, Crowe et al. 2009).

Achim, C. L., A. Adame, et al. (2009). "Increased accumulation of intraneuronal amyloid beta in HIV-infected patients." J Neuroimmune Pharmacol 4(2): 190-9. Anthony, I. C., S. N. Ramage, et al. (2006). "Accelerated Tau deposition in the brains of individuals infected with human immunodeficiency virus-1 before and after the advent of highly active anti-retroviral therapy." Acta Neuropathol 111(6): 529-38. Antinori, A., G. Arendt, et al. (2007). "Updated research nosology for HIV-associated neurocognitive disorders." Neurology 69(18): 1789-99. Ayhan, F., F. Soyupek, et al. (2007). "Decreased handgrip strength and increased hip osteoporosis in patients with Alzheimer`s disease." Neurosciences (Riyadh) 12(2): 140-4. Baltes, P. B., U. M. Staudinger, et al. (1999). "Lifespan psychology: theory and application to intellectual functioning." Annu Rev Psychol 50: 471-507. Bumler, G. (1985). Farb-Wort-Interferenztest (FWIT). Gttingen, Toronto, Zrich, Hogrefe. Becker, J. T., L. Kingsley, et al. (2009). "Vascular risk factors, HIV serostatus, and cognitive dysfunction in gay and bisexual men." Neurology 73(16): 1292-9. Brew, B., Gisslen M., Pemberton, L., Cinque, P., Hagberg, L., Price, R., Blennow, K., Zetterberg, H., Spudich, S. (2008). CSF t-tau, p-tau and Amyloid-beta 1-42 in HIV Infection. 15th Conference on Retroviruses and Opportunistic Infections Boston, MA: #395. Brew, B. J., S. M. Crowe, et al. (2009). "Neurodegeneration and ageing in the HAART era." J Neuroimmune Pharmacol 4(2): 163-74. Brew, B. J., L. Pemberton, et al. (2005). "CSF amyloid beta42 and tau levels correlate with AIDS dementia complex." Neurology 65(9): 1490-2. Brickenkamp, R. (1994). Test d2 Aufmerksamkeits-Belastungstest. Gttingen, Bern, Toronto, Seattle, Hogrefe. Chang, L., P. L. Lee, et al. (2004). "A multicenter in vivo proton-MRS study of HIVassociated dementia and its relationship to age." Neuroimage 23(4): 1336-47. Clifford D, K. J., Teshome M, Shah A, Spinner M, Morris J, Holtzman D, Fagan A (2008). Abnormal CSF amyloid beta42 levels link HIV-associated cognitive disease and Alzheimers disease. 15th Conference on Retroviruses and Opportunistic Infections. Boston, MA: #396b. Deeks, S. G. (2009). "Immune dysfunction, inflammation, and accelerated aging in patients on antiretroviral therapy." Top HIV Med 17(4): 118-23. Dietz, C. A. and C. R. Nyberg (2011). "Genital, oral, and anal human papillomavirus infection in men who have sex with men." J Am Osteopath Assoc 111(3 Suppl 2): S19-25. Fishman, S. L., J. M. Murray, et al. (2008). "Molecular and bioinformatic evidence of hepatitis C virus evolution in brain." J Infect Dis 197(4): 597-607. Gannon, P., M. Z. Khan, et al. (2011). "Current understanding of HIV-associated Page 10 of 26

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neurocognitive disorders pathogenesis." Curr Opin Neurol 24(3): 275-83. Gongvatana, A., B. C. Schweinsburg, et al. (2009). "White matter tract injury and cognitive impairment in human immunodeficiency virus-infected individuals." J Neurovirol 15(2): 187-95. Goulet, J. L., S. L. Fultz, et al. (2007). "Aging and infectious diseases: do patterns of comorbidity vary by HIV status, age, and HIV severity?" Clin Infect Dis 45(12): 1593601. Green, D. A., E. Masliah, et al. (2005). "Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients." Aids 19(4): 407-11. Hahn, K., M. Sirdofsky, et al. (2006). "Collateral sprouting of human epidermal nerve fibers following intracutaneous axotomy." J.Peripher.Nerv.Syst. 11(2): 142-147. Hahn, K., A. Triolo, et al. (2007). "Impaired reinnervation in HIV infection following experimental denervation." Neurology 68(16): 1251-6. Hoare, J., J. P. Fouche, et al. (2010). "White matter correlates of apathy in HIV-positive subjects: a diffusion tensor imaging study." J Neuropsychiatry Clin Neurosci 22(3): 313-20. Ikemura, M., Y. Saito, et al. (2008). "Lewy body pathology involves cutaneous nerves." J Neuropathol Exp Neurol 67(10): 945-53. Jellinger, K. A. (2011). "Synuclein deposition and non-motor symptoms in Parkinson disease." J Neurol Sci. Joska, J. A., H. Gouse, et al. (2010). "Does highly active antiretroviral therapy improve neurocognitive function? A systematic review." J Neurovirol 16(2): 101-14. Kaul, M., G. A. Garden, et al. (2001). "Pathways to neuronal injury and apoptosis in HIVassociated dementia." Nature 410(6831): 988-94. Loring, D. W., R. C. Martin, et al. (1990). "Psychometric construction of the Rey-Osterrieth Complex Figure: methodological considerations and interrater reliability." Arch Clin Neuropsychol 5(1): 1-14. Lovden, M., S. C. Li, et al. (2007). "Within-person trial-to-trial variability precedes and predicts cognitive decline in old and very old age: longitudinal data from the Berlin Aging Study." Neuropsychologia 45(12): 2827-38. McArthur, J. C., J. Steiner, et al. (2011). "Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap." Ann Neurol 67(6): 699-714. Minagar, A., P. Shapshak, et al. (2002). "The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis." J Neurol Sci 202(1-2): 13-23. Nagel, I. E., C. Chicherio, et al. (2008). "Human aging magnifies genetic effects on executive functioning and working memory." Front Hum Neurosci 2: 1. Nolting, T., A. Lindecke, et al. (2009). "Measurement of soluble inflammatory mediators in cerebrospinal fluid of human immunodeficiency virus-positive patients at distinct stages of infection by solid-phase protein array." J Neurovirol 15(5-6): 390-400. Onen, N. F. and E. T. Overton (2011). "A review of premature frailty in HIV-infected persons; another manifestation of HIV-related accelerated aging." Curr Aging Sci 4(1): 33-41. Pattullo, V., M. P. McAndrews, et al. (2011). "Influence of hepatitis C virus on neurocognitive function in patients free from other risk factors: validation from therapeutic outcomes." Liver Int 31(7): 1028-38. Rao, V. R., A. R. Sas, et al. (2008). "HIV-1 clade-specific differences in the induction of neuropathogenesis." J Neurosci 28(40): 10010-6. Ruff, R. M., R. H. Light, et al. (1996). "Benton Controlled Oral Word Association Test: reliability and updated norms." Arch Clin Neuropsychol 11(4): 329-38. Sacktor, N. C., R. H. Lyles, et al. (1999). "Combination antiretroviral therapy improves psychomotor speed performance in HIV-seropositive homosexual men. Multicenter AIDS Cohort Study (MACS)." Neurology 52(8): 1640-7. Sokolova, A., M. D. Hill, et al. (2009). "Monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in Alzheimer's disease." Brain Pathol 19(3): 392-8. Spreen, O., Strauss, E. (1991). A compendium of neuropsychological tests. New York, Page 11 of 26

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Oxford, Oxford University press. Ting, K. K., B. Brew, et al. (2007). "The involvement of astrocytes and kynurenine pathway in Alzheimer's disease." Neurotox Res 12(4): 247-62. Tisch, S. and B. Brew (2009). "Parkinsonism in hiv-infected patients on highly active antiretroviral therapy." Neurology 73(5): 401-3. Town, T., Y. Laouar, et al. (2008). "Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology." Nat Med 14(6): 681-7. Valcour, V., C. Shikuma, et al. (2004). "Higher frequency of dementia in older HIV-1 individuals: the Hawaii Aging with HIV-1 Cohort." Neurology 63(5): 822-7. Valcour, V., P. Sithinamsuwan, et al. (2011). "Pathogenesis of HIV in the central nervous system." Curr HIV/AIDS Rep 8(1): 54-61. Valcour, V. G., N. C. Sacktor, et al. (2006). "Insulin resistance is associated with cognition among HIV-1-infected patients: the Hawaii Aging With HIV cohort." J Acquir Immune Defic Syndr 43(4): 405-10. Van der Elst, W., M. P. van Boxtel, et al. (2005). "Rey's verbal learning test: normative data for 1855 healthy participants aged 24-81 years and the influence of age, sex, education, and mode of presentation." J Int Neuropsychol Soc 11(3): 290-302. Wakabayashi, K., F. Mori, et al. (2011). "Involvement of the peripheral nervous system in synucleinopathies, tauopathies and other neurodegenerative proteinopathies of the brain." Acta Neuropathol 120(1): 1-12. Xu, J. and T. Ikezu (2009). "The comorbidity of HIV-associated neurocognitive disorders and Alzheimer's disease: a foreseeable medical challenge in post-HAART era." J Neuroimmune Pharmacol 4(2): 200-12. Yepthomi, T., R. Paul, et al. (2006). "Neurocognitive consequences of HIV in southern India: a preliminary study of clade C virus." J Int Neuropsychol Soc 12(3): 424-30.

2. Description of the aims

Aim No. 1 2 3 4 5 6 Description Clinical characterisation Virological characterisation Characterisation of the lipid profile Neurodegeneration in CSF and skin biopsy Immunoactivation in CSF, APOE4 Risk factors (subtyping of HIV) Participant(s) responsible for the aim / workload Endres Hofmann, Jrg Steinhagen-Thieen Hahn Arendt Cinque

3. Workplan (max. 15 pages), it must contain:

a. Description of the working program including the objectives, the rationale and the methodology, highlighting the novelty, originality and feasibility of the project b. Clearly define the responsibilities and workloads [expressed in person months] of each participating research group, time plan, project coordination and management c. References d. Diagrams and figures

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A Patient cohort study

A cohort of about 100 HIV-infected elderly persons (older than 50years) in Germany and around 50 patients in Turkey is going to be established and followed up longitudinally focussing on cardiovascular diseases, metabolic diseases, diseases of the musculoskeletal system/lipid distribution, degenerative diseases of the CNS as well as changes in the adaptive immune system. Patients are going to be seen at the primary investigation within the first year to undergo a comprehensive study program which will be repeated every two years. As there is an intercultural exchange especially in Berlin it is important to get knowledge about the ageing Turkish population as well. A partnership and clinical exchange with the University of Akdeniz in Antalya is already established. This cohort will be compared to a group of an already existing cohort of elderly non HIV-infected persons from Berlin (BASE I and BASE II study) which is being followed multidisciplinary combining behavioural sciences, social sciences, and medical- neurological scientific science as well as to the Dsseldorf HIV-cohort (Prof. Dr. Arendt). So far 2200 randomly selected persons have been seen seven times during BASE I and 5000 patients are in the Dsseldorf HIV-cohort including around 650 patients over 50 years old. Investigation of intellectual and physical development in seniority is based on five conceptual empiric challenges (Baltes, Staudinger et al. 1999). Firstly alterations of several functional areas have to be interlinked. Here we are going to focus on sensory, motoric and intellectual capacity. Second time scales of capacities have to be combined as it was shown that acute fluctuations of cognitive capacities correlate with an increased cognitive degradation in the following years (Lovden, Li et al. 2007).Thirdly, for the determination of biological courses and impact on the development on behaviour and assimilation and its interaction with social circumstances it is necessary to combine changes in behaviour with neuronal processes with the general state of health. For that the genetic background has to be determined. So genetic traits can contribute to distinctions in aging devolution. (Nagel, Chicherio et al. 2008). Fourthly, the intellectual and physical development in age is not determined. The behaviour plasticity and its connection to neuronal mechanisms are going to be determined through interventions. Fifthly a longitudinal study is necessary to investigate the bandwidth of aging on the individual phenotype within a cohort of a variety of demographic and biographic differing persons as it is possible in Berlin and Antalya.
0-12 months: Patient recruitment:

Contact of ambulatory care HIV-physicians by visits and introduction of the project through the study group. Eligible persons are going to be referred to the study center. First contact of patients by a telephone interview, appointment of the first study visit:

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Day 0 First visit of the patient at the ambulatory care department of the EGZB

1. Past medical history 2. Acute complaints 3. Introduction of the study/Information on the home care physician 4. Physical examination 5. Neurological examinations 6. Blood examination clinical chemistry hematologic assays lipid analyses, immune status

7. Virological evaluation serological and nucleic amplification of HIV serological and nucleic amplification of HCV, VZV and HBV

8. Comprehensive neuropsychological assessment Rationale: HAND is a clinical neurology diagnosis. The syndrome is characterized by neurocognitive impairment (e.g. memory disorders, concentration disorders, psychomotor retardation), affective/emotional disorders (e.g. apathy, social withdrawal) and motor dysfunction (tremor, spasms, drug-induced parkinsonism). In order to assess HAND a quite standardized comprehensive neuropsychological assessment is necessary.

(Antinori, Arendt et al. 2007) Methodology:

- d2 test (concentration, psychomotor speed) (Brickenkamp 1994) - Rey word list (attention, verbal learning and memory) (Spreen 1991; Van der Elst, van Boxtel et al. 2005) - Rey figure list (attention, figural learning and memory) (Spreen 1991)

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- Rey Osterreith complex figure test (visuoconstructive abilities, memory) (Loring, Martin et al. 1990) - Stroop color-word interference test (abstraction, executive function) (Bumler 1985) - S test (verbal fluency) (Ruff, Light et al. 1996) - Grooved pegboard test (motor skills) (Sacktor, Lyles et al. 1999) 8. Geriatric depression scale

9. MMSE 10. Attachment of a movement belt for one week

Day 7 Second visit one week later at ambulatory care department of the EGZB

1. Glucose tolerance test Rationale: Elevated fasting glucose, insulin resistance and, separately, diabetes correlated to poorer overall cognitive performance in the Hawaii Aging with HIV Cohort (HAHC) study (Valcour, Sacktor et al. 2006). 2. Lipid analysis: Cholesterol, LDL, HDL, Apo lipoprotein B. Apo A1, Lp(a) 3. Blood draw for genomic screeninig (MPI) immunologic assays/ immune phenotyping (Tbingen) Methodology: nave-phenotype (CD45RA+CCR7+CD27+CD28+), central memory TCM (CD45RACCR7+ CD27+CD28+), effector memory TEM (CD45RA- CCR7-CD27+/-CD28+/-) and TEMRA (CD45RA+ CCR7-CD27+CD28+/-) phenotype, expression of CD57 and KLRG-1, phenotypic CD4 regulatory T cells (CD4+Foxp3+CD127loCD25high) and CD8 suppressor T-cells (CD8+CD103+, CD8+Foxp3+) 4. Measurement of the bone densitiy by DEXA scan 5. Serological assesment of HIV serology, by ELISA, immoblot, RNA concentration and proviral DNA concentration 6. Serological assessment of HCV, HBV, HGV, HEV by serology and nucleic acid amplification techniques (PCR) Rationale: HCV itself can influence neurocognitive function. (Fishman, Murray et al. 2008; Pattullo, McAndrews et al. 2011) To 7. genome-wide association study Rationale: To investigate genetic variations associated with any particular disease Methodology: EDTA-Blood is transferred to the MPI for Molecular Genetics , DNA is isolated and analysed by Affymetrix GeneChip Mapping 500 K Array.
8. Urological sonographic and gynaecologcal examination to assess human papillomavirus infection Rationale: As papilomaviruses are transmitted by direct contact and are oncogenic viruses the burden of

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infection is going to by characterized in healthy and infected persons to assess their risk of epithelial cancers in the oral and urogenital mucosa. The epidemiolgy in old persons is not known so far, and the mode of transmission is discussed controversially.(Dietz and Nyberg 2011). Methodology: To assess possible incontinence and renal insufficiency in male and female a urological examination with a sonogram is performed at the EGZB. Swabs are taken for Human papillomavirus infection. Incontinence is going to be assessed by PCR amplification of swabs. Additionally swabs are taken from the oropharynx as carcinogenic potential and distribution of viral infection is going to be characterized.

9. Doppler sonography of the carotid vessels Rationale: Only a very few groups have demonstrated relationships between atherosclerotic risk and cognition. The Multicenter AIDS Cohort Study (MACS) identified a relationship between carotid endothelial thickness and cognition (Becker, Kingsley et al. 2009). Methodology: Ultrasound examination of the carotid artery will be used to quantify intima-media thickness (IMT). 10. Lung function analysis, spirometry 11. Ecg, and long duration ecg for 3 hours 12. Bioelectric impedance measurement 13. Anthropometry Rationale: To determine the sceletal muscle mass. BIA and anthropometric measurements are used to measure the total muscle mass. Sarcopenia and fraility are going to be assessed to determine their posssible predictive value for and death and home care demand

14. Pulse oxymetric measurement 15. Hand grip strength/Digitometry Rationale: handgrip strength may be an easy to perform marker for osteoporosis (Ayhan, Soyupek et al. 2007). The value of its prediction in HIV infected persons is unknown. Methodology: A manometer is used for the handgrip determination. 16. Orthostasis test (Schellong test) 17. Tinetti Mobility Test/Timed up an go test Methodology: TinettiTest and Timed up and go test are used to assess the danger of a possible downfall 18. audiometric investigastion Rationale: The seroprevalence of HIV among the deaf and hard of hearing persons is not known. This study is going to deliver estimations how high an hearing impairment is in the community of HIV infected persons. 19. Vision assessment 20. Cerebral MRI (J. Fiebach) Rationale: New imaging modalities have extended beyond structural MRI and show promise in HAND. Diffusion tensor imaging (DTI) measures the microstructural diffusion of water in the brain, a Page 16 of 26

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sensitive measure for injury within white matter tracts (Valcour, Sithinamsuwan et al. 2011). Abnormalities in DTI are noted in HIV with clinical correlates, but are also noted in asymptomatic subjects (Gongvatana, Schweinsburg et al. 2009; Hoare, Fouche et al. 2010). Methodology: Subjects undergo structural MRI measurement of the brain using a 3 Tesla MRI scanner (Siemens). T1-weighted 3D sequencing with isotropic resolution of 1 x 1 x 1 mm (or 0.5 x 0.5 x 0.5 mm), axial FLAIR imaging and DT1 sequencing (diffusion tensor imaging) will be done.
18. Cytokine and apolipoprotein E4 analysis in the CSF (Arendt)

Rationale: With respect to the neuropathogenesis of HIV-associated dementia infectious (directly virus related) and immune pathomechanisms are discussed (Kaul, Garden et al. 2001). Chang et al. discuss a more robust neuro-inflammatory response in younger relative to older HIV-positive individuals. In MRI-studies this group had shown greater elevations in glial and lower neuronal markers in younger than in older HIV-positive individuals (Chang, Lee et al. 2004). In cell culture studies enhanced immune responses with increased production of microglial pro-inflammatory markers (NO, TNF-alpha, IL-12 and IL-6) were observed (Vitek et al., 2009). Glial activation may be protective or lead to overstimulation of the neuro-inflammatory pathways and thus to severe brain damage. Whether age is a risk factor for inflammatory brain damage or whether genetic predisposition (APOE 4 expression) plays a role should be subject to research . Methodology: cytokine and APOE4 expression analysis in CSF as well as measurements cellularity, Protein concentration, p Protein differentiation by Reiber's method (blood-brain barrier function, autochthonous immunoglobulin synthesis), isoelectric focusing (autochthonous IgG synthesis), CSF Neopterin.

21. Genotyping/env analyzing (Cinque)

22. Neurodegenerative proteins in the CSF Rationale: There have been several studies establishing a neuropathologically link between

Alzheimer disease and HAND. The following table is part of a review from Brew et al. summarizing them (Brew, Crowe et al. 2009).

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However there are inconsistent data investigating the concentration of neurodegenerative proteins such as Amyloid beta 1-42, t-tau as well as p-tau in patients with HAND in the CSF. The levels were in general comparable to those of Alzheimer patients except that the p-tau values were normal (Brew 2008; Clifford D 2008). There is however one study showing raised t-tau as well as p-tau in patients with HAND (Brew, Pemberton et al. 2005). Methodology: - concentrations of amyloid beta 1-42, t-tau, p-tau in the CSF

23. Skin biopsy (Hahn) Rationale: It is uncertain whether cognitive dysfunction reflects accelerated neuropathological processes associated with HAND or with other neurodegenerative diseases such as Alzheimers disease or Parkinsons disease. Tisch et al describe increased levels of alpha-synuclein (Syn) in the substantia nigra associated with an increased risk for Parkinsons disease in aging HIV positive patients on antiretroviral therapy (Tisch and Brew 2009). Alpha-synuclein as a hallmark in Parkinson disease (PD) and other synucleinopathies is distributed throughout the nervous system, including the central nervous system, (CNS), sympathetic ganglia, enteric nervous system, cardiac and pelvic plexuses, submandibular gland, adrenal medulla and skin (Jellinger 2011; Wakabayashi, Mori et al. 2011). Ikemura et al. prospectively and retrospectivly examined samples from the abdominal skin and upper limb and demonstrated that the sensitivity of Lewy pathology in the skin was 70% in Parkinson disease (Ikemura, Saito et al. 2008; Wakabayashi, Mori et al. 2011). To our knowledge alpha-synuclein was never investigated in skin biopsies from HIV-infected individuals. We aim to answer the question: Is there evidence of alpha-synuclein or Lewy pathology in skin biopsies of neurocognitively impaired HIV infected individuals? Methodology: We perform 3mm biopsies at the abdominal skin and the lower limb. The biopsies Page 18 of 26

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were processed for visualization of IENF as previously described (Hahn, Sirdofsky et al. 2006; Hahn, Triolo et al. 2007) as well as immunostained for alpha-synuclein (Ikemura, Saito et al. 2008).

4. Diagram which compiles the work plan, the contribution of the partners to each

work package and their interactions (max. 1 page)

6 Months Physician Bioinformatic Specialist Student worker Recruitment in Germany and in Turkey Recruitment of the Second followup in Germany and Turkey Physical examinations Physical CSF ecxaminations in examinations Dsseldorf and in Italy CSF cns imaging ecxaminations in Dsseldorf and in Italy cns imaging Virological Virologic Virological examinations in examinations in al Italy and at the Italy and at the examina tions in Charit Charit Italy and Immunological Immunological at the examinations of examinations of Charit the peripheral the peripheral Immunol blood blood ogical examina tions of the peripher al blood Building up the database, analysis of the data Recruitment of the first follow- up in Germany and Turkey Physical examinations CSF ecxaminations in Dsseldorf and in Italy cns imaging 1 2 3 4 5 6 7 8 9 10

Workplan

5. Added value of the proposed transnational collaboration (max. 1 page)

The cns pathology of the HIV is very excellent performed in Italy. There the noew possible HIV circulating forms can be easily described in their immunological behaviour. In Turkey there is an underestimation of the HIV-prevalence. In a General medicine Department of a Page 19 of 26

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University clinic there is a high chance to collect infected patients as there they are not prejudiced in attending the General Medicine Clinic. HIV-typing and immunological analysis are going to be performed by German and Italian reference laboratories. The reference laboratories benefit from a new collection of HIV strains.

6. Potential health impact and exploitation / dissemination of project results (max. page)
The data of the analysis is going to be presented on the BASE homepage which is already excisting. It is going to be summarized into a book.

7. Description of patents and present / future position with regard to intellectual property rights, both within and outside the consortium (e.g. any barriers to sharing materials or results) (max. page)
There are now barriers to share materials and results. For the BASE study the data from all occasions of measurement are collected in a well-documented central database. Their documentation can be obtained from the Project Coordination office , Max Planck Institute for Human Development, Lentzeallee 94, 14195 Berlin, Germany. External scientists can apply for the use of data by submitting a written application for the transfer of BASE data for use in scientific analyses to the Project Coordination. The application should detail (a) the research questions to be examined and/or analyses to be carried out and (b) the variables required. The application is reviewed before data can be provided according to the rules of German data protection laws

8. Description of ongoing research projects of each participating group related to the present topic (indicating funding sources [include at least: ID number, amount and duration of funded project; funding agency] and possible overlaps with the proposal) (max. page per research group)
The Berlin Aging Study is a multidisciplinary investigation of old people aged 70 to over 100 years who live in former West Berlin. In the main study (1990-1993), a core sample of 516 individuals was closely examined in 14 sessions covering their mental and physical health, their psychological functioning, and their social and economic situation. Since then, the study has been continued as a longitudinal study, and surviving participants have been reexamined seven times . BASE is a project conducted by several Berlin institutions in collaboration. It was supported by the Federal Ministry for Family Affairs, Senior Citizens, Women and Youth (in German) and by the Berlin-Brandenburg Academy of Sciences' interdisciplinary research group "Aging and Societal Development", and the participating institutions. Since 2008, it is co-sponsored by the Federal Ministry of Education and Research and the Center of Lifespan Psychology at the Max Planck Institute for Human Development

9. Scientific justification of requested budget (please also specify co-funding from other sources necessary for the project if applicable) (max. page per research group)
So far there is no knowledge on the disease burden and the natural progression of life in the aging society. HIV infected persons get older than 20 years before. So far there is no longitutindal observed cohort in which the mechanisms of aging are observed. As there is a close intersocial exchange between persons of German and Turkish descent in Berlin and in the vacation area of Antalya new HIV circulating recombinant forms with a specific pathogenicity can evolve. Therefore a cohort from Berlin and a cohort from Antalya with documentation of the medical history, with physical examination of the respiratory system, the cardiovascular system, the motor activity, sociological description give the opportunity to estimate the disease burden of the future generation of HIV infected senior citicens. Page 20 of 26

HIVERA JTC 2011-Full-proposal application form

10. Ethical and legal issues - according to national regulations if applicable (e.g. informed consent, data protection, use of animals)
For the BASE-study which is the proposed study is referring to there is an Ethical consent existent. The genetic analyses are licensed.

11. Brief CVs for each participating group leader (with a list of up to five relevant publications within the last five years demonstrating the competence to carry out the research project) (max. 1 page per group leader)
Anne-Sophie Endres Personal Data Dr. med. Anne-Sophie Endres, geb. Gericke Email: anne-sophie.endres@egzb.de Date of birth: 29.12.1967 married, three children evangelical lutheran School 1974-1978 1978-1980 1980-1988 1984/1985 1998 1988-1990 1990-1993 10/1993- 4/1994

5/1995 6/1996 4/1997-6/1997 14.11.2006 21.11.2007 Experience 4/1994-7/1995 8/1995-2/1996 4/1996-4/1997 4/1997-6/1997 7/1997-9/1998 1/1999-2/1999 2/1999-3/1999 3/1999-12/1999 1/2000-3/2000 4/2000-5/2006

Elementary school, Nordenham Orientierungsstufe, Nordenham Gymnasium Nordenham exchange year in Washington State, USA Abitur Medicine, preclinical studies at the CAU, Kiel Clinical part of medicine at the University of Hamburg Thesis: Isoenzymanalyse von Blastocystis hominis under the supervision of Professor J. Knobloch, Institut fr Tropenmedizin, Tbingen 3. Staatsexamen USMLE Diploma for Tropical Medicine and Hygiene at the Bernhard Nocht Institut, Hamburg qualification as a consultant for microbiology, virology and epidemiology Certificate for Travelmedicine Travel medicine at the Tropeninstitut Tbingen Medicine for the Komitee rzte fr die Dritte Welt at a health center in Manila, Philippines Tropical medicine at the Tropenklinik-Paul-Lechler-Krankenhaus, in Tbingen Diploma for Tropical Medicine at the Bernhard Nocht Institut,Hamburg Residency for Medicine / Infectious Diseases at the State University of New York, Brooklyn, USA Work experience or the Deutscher Entwicklungsdienst Prepartion of the congress: 9. ECCMID in Berlin for Professor Lode Assistent of Professor Weibach, former President of the Deutschen Krebsgesellschaft, as ghostwriter Urology at the department for urology for Professor Weibach at the Urban Krankenhaus, Berlin Research assistant und resident at the Institut fr Page 21 of 26

HIVERA JTC 2011-Full-proposal application form

5/2006 5/2007 10/2007 -03/2011 2/2009-3/2009 03/2011

Virologie, Professor Krger, Charit, Berlin Research assistant at th Robert Koch-Institut in the work group for antibiotic resistance surveillance Head of the section for molecular diagnosis of infectious diseases at the Institut fr Medizinische Diagnostik, Berlin, Germany Tropical Medicine excursion to Uganda Medical resident at the Evangelisches Geriatriezentrum Berlin

Professor Gabriele Arendt, MD 12/11/1954 born in Duesseldorf, Germany 1961-1965 Albert-Schweitzer elementary school, Duesseldorf 1965 -1973 Clara-Schumann High school, Duesseldorf 1973-1979 Medical School Johannes Gutenberg University Mainz and Heinrich Heine University Duesseldorf 11/1979 Medical Approbation 11/1980 American State examination (ECFMG) 1981 Doctoral thesis (Radioimmunoassay of serum digoxine methodological problems and correlation to clinical parameters 1981-1883 junior doctor in psychiatry, Department of Psychiatry, University of Duesseldorf 1984-1989 junior doctor in neurology, Department of Neurology, University of Duesseldorf, Director: Professor Hans-Joachim Freund 1987 national board exams as psychiatrist and neurologist 1/9/1987 senior registrar Department of Neurology, University of Duesseldorf 11/1987 foundation of a Neuro-AIDS Ambulance integrated in the Department of Neurology; clinical, neurophysiological and neuro-imaging studies on HIV infection, studies on basal ganglia dysfunction and studies on therapy effects on the nervous system; cell culture experiments on cellular effector- and immunologic regulation mechanisms in HIV infection together with H. Koeller, MD 1994 university thesis (The significance of quantifying electrophysiological motor tests for the course of HIV-1-associated brain disease) 1997 assistant professor, Department of Neurology, University of Duesseldorf 2000 associate professor, Department of Neurology, University of Duesseldorf 2002 chairman of the 4th international symposium of the ISNV held conjointly with the 10th conference on neuroscience of HIV-infection Membership in Editorial boards of international journals Journal of Neuro-AIDS Society Memberships since 1982 Neurological society of Duesseldorf since 1986 International Federation of Clinical Neurophysiology since 1997 German Neurological society since 1999 Founding member of the German Neuro-AIDS Working group Founding member of the the International Society of Neurovirology (ISNV) since 1999 Membership in the working group for Intensive care medicine since 2000 Membership in the German AIDS society since 2002 Membership in the German Competence Network HIV/AIDS since 2004 Editorial board membership J NeuroVirol since 10/2007 Speaker of the Clinical Science Board German Competence Page 22 of 26

HIVERA JTC 2011-Full-proposal application form

until 09/2011 Network HIV/AIDS

Katrin Hahn, MD E-Mail: katrin.hahn@charite.de

06/08/1971 1991-1997 2/1998 1998 9/1999-4/2003

born in Finsterwalde, Germany Medical School Humboldt University Berlin Medical Approbation Doctoral thesis (magna cum laude) junior doctor in neurology, Department of Neurology, Charit Universittsmedizin Berlin, Director: Professor K.M. Einhupl

11/2003 10/2005

Grant from the German Research Foundation and post-doc in the skin lab and HIV lab at the Department of Neurology Johns

Hopkins University Baltimore/USA (Prof. Nath and Prof. J. McArthur) 11/2007 2/2008 1/2010 national board exams as neurologist Rahel Hirsch grant Charit Universittsmedizin Berlin

Since 9/2009 Oberrztin and head of the electrophysiology lab, Department of Neurology, Charit Universittsmedizin Berlin, Director: Professor M. Endres

Paola Cinque,

San Raffaele Scientific Institute, Milano, Italy

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12. Financial plan: sum of year 1-5. Please describe the requested budget only
Acronym: No. Name (principal investigator) Funding organization Person Months, (1)* Person Months, (2) Person Months, (3) Person Months, (4) Personnel total Consumables Equipment Travel ** Other direct costs *** 360000 Overheads **** Total requested 1764562,16 30000 30 000 1764562,16 100000 budget * Please detail number of person months (PM), qualification (Si: scientist, e.g. postdoc; PhD-student; N: non-scientist, e.g. technician; Ot: other) and requested. Please use one cell per person to provide this information. Please note that students are funded according to national regulations **Travel expenses should include the participation of the coordinators and/or national group leaders at an intermediate and/or a final status symposium to present the results of their projects (organized by the Joint Call Secretariat) ***e.g. subcontracting, provisions, licensing fees; may not be eligible costs in all countries (will be handled according legal framework and funding body regulations)
* * *

Project coordinator Anne-Sophie Endres BMBF 60, 150.000 36, 196562,16, 36, 39.000 385562,16 605000 514000

Partner 2 Katrin Hahn

Partner 3 Gabriele Arendt

Partner 4 Hakan Yaman

Partner 5 Paola Cinque

Partner 6

BMBF

BMBF

The Scientific and Technological Istituto Superiore Research Council di Sanita of Turkey

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****Overhead costs: funding according to national legal framework and funding body regulations. Please refer to the guidelines for applicants for full proposal application form

13. Number of person months (PM) of personnel participating in the project for which no funding is requested (if applicable). Please detail number of person months (PM) and the qualification (Si: scientist, e.g. postdoc; PhD-student; N: non-scientist, e.g. technician; Ot: other).
No. Funding organization Person Months (1) Person Months (2) Person Months (3) Person Months (4) Project coordinator Partner 2 Partner 3 Partner 4 Partner 5 Partner 6

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