Dementia – Diagnostic and Therapeutic Interventions A Systematic Review Volume 2 June 2008 The Swedish Council on Technology Assessment in Health Care SBU • Statens beredning för medicinsk utvärdering SBU Evaluates Healthcare Technology SBU (the Swedish Council on Technology Assessment in Health Care) is a government agency that assesses the methods employed by medical professionals and institutions. In addition to analyzing the costs and benefits of various health care measures, the agency weighs Swedish clinical practice against the findings of medical research. The objective of SBU’s activities is to provide everyone who is involved in decisions about the conduct of health care with more complete and accurate information. We welcome you to visit our homepage on the Internet at www.sbu.se. SBU issues three series of reports. The first series, which appears in a yellow binding, presents assessments that have been carried out by the agency’s project groups. A lengthy summary, as well as a synopsis of measures proposed by the SBU Board of Directors and Scientific Advisory Committee, accompanies every assessment. Each report in the second, white-cover series focuses on current research in a parti- cular healthcare area for which assessments may be needed. The Alert Reports, the third series, focus on initial assessments of new healthcare measures. To order this report (No 172E/2) please contact: SBU Mailing Address: Box 5650, SE-114 86 Stockholm, Sweden Street Address: Tyrgatan 7 Tel: +46 8 412 32 00 Fax: +46 8 411 32 60 Internet: www.sbu.se E-mail: [email protected] Graphic Design: pmochco, www.pm.se Printing: Elanders Infologistics Väst AB, Mölnlycke 2008 ISBN 978-91-85413-24-9 • ISSN 1400-1403 Dementia – Diagnostic and Therapeutic Interventions A Systematic Review Project Group Olof Edhag Laura Fratiglioni Anders Norlund (Chair) Lars Gustafson (Project Director) Hedda Aguero-Eklund Ingrid Håkanson Liisa Palo-Bengtsson Ove Almkvist (Project Assistant) Magnus Sjögren Kenneth Asplund Aki Johanson Eva von Strauss Kaj Blennow Ingvar Karlsson Lars-Olof Wahlund Sirkka-Liisa Ekman Mona Kihlgren Gunhild Waldemar Knut Engedal Lena Kilander Anders Wallin Elisabet Englund Elisabet Londos Anders Wimo Sture Eriksson Jan Marcusson Dag Årsland Johan Fastbom Astrid Norberg Scientific Reviewers Per Edebalk Rurik Löfmark Anneli Sarvimäki Serge Gauthier Hans Melander Hilkka Soininen Lars Lannfelt Ingalill Rahm Matti Viitanen Kim Lützén Hallberg Reference Group Ann Hedberg Balkå P-O Sandman Bengt Winblad (Swedish Association (Umeå University) (Karolinska Institute) of Local Authorities Members from the and Regions) Alzheimer Associ- ation of Sweden and from the Dementia Association The Swedish Council on Technology Assessment in Health Care SBU • Statens beredning för medicinsk utvärdering Content 9. Diagnosing Dementia Disorders 17 Background 17 Diagnostic evaluation of dementia 17 The concept of mild cognitive impairment (MCI) 17 Guidelines for the diagnostic evaluation of dementia 19 European federation of neurological societies (EFNS) 19 guidelines [3] American Academy of Neurology guidelines [5] 20 Aims 21 Methods 21 Selection of papers 21 Classification of evidence 27 Summary of evidence 28 Laboratory screening tests that might detect 28 reversible cognitive impairment Tests that can be used to detect a dementia disorder 28 Single cognitive tests 28 Tests that identify specific dementia disorders 29 ApoE 29 Methods of diagnosing dementia disorders 29 Structural imaging (MRI/CT) 29 Functional imaging (PET, SPECT) 29 Neurophysiological methods (EEG, EEG) 29 CSF analyses 29 Methodological considerations 30 Lack of gold standard 31 Selection bias 31 Setting 31 Circularity bias 32 Recommendations for future research 32 References 34 Checklists regarding assessment of study quality for different chapters of this report are included in the electronic version of the SBU report on Dementia diseases at www.sbu.se 10. Identifying Secondary Dementia or Potential Reversible 35 Cognitive Impairment Thyroid disease and dementia 35 Background 35 Literature search for evidence 35 Search strategy 36 Results 36 Comments 37 References 46 11. Neurosyphilis and Dementia 49 Background 49 Literature search for evidence 50 Search strategy 50 Result 51 Comments 51 References 56 12. Vitamin B12, Folic Acid and Homocysteine, 57 Cognitive Impairment and Alzheimer’s Disease Conclusions 57 Background 57 Literature search strategy 58 Comments 60 Vitamin B12 60 Folic acid 60 Homocysteine 60 Treatment with vitamin B12 or folate 60 References 76 13. Evidence for Tests that can be used to Diagnose Dementia 79 Informant interview in the diagnostic 79 evaluation of patients with dementia Background 79 Literature search 80 Search strategy 80 Results 80 Comments 81 References 88 14. Neuropsychological Tests as a Diagnostic Marker 91 of Dementia Conclusion 91 Introduction 91 Aim 91 Search strategy 92 Description of studies included and excluded 92 Results 93 Discussion 94 References 102 15. Evidence-based Evaluation of Single Cognitive Tests 103 as a Diagnostic Marker of Dementia Conclusions 103 Introduction 103 Search strategy 104 Results 105 Discussion 106 References 116 16. Genetic Markers 119 Conclusion 119 Causative genes for dementia disorders 119 Apolipoprotein E ε4 as a diagnostic marker of AD 120 Background 120 Literature search strategy 122 Results 122 ApoE ε4 allele as a marker of AD 123 in comparison with controls ApoE ε4 allele as marker of AD compared 124 to other dementia disorders ApoE ε4 allele as marker of AD compared to MCI 125 ApoE ε4 allele as marker of FTLD compared 125 to normal controls References 162 17. Structural and Functional Imaging of the Brain 171 in Dementia Workup Conclusions 171 Introduction 172 Search strategy 172 Structural imaging 173 Results 173 References 188 18. Functional Imaging’s Diagnostic Tool in Dementia 193 Workup Search Strategies Conclusions 193 Introduction 193 Search strategy 194 Results 195 References 208 19. Evidence Based Evaluation of EEG (Quantitative EEG 211 and Visual Rated EEG) Conclusions 211 Introduction 211 Search strategy 211 References 218 20. Cerebrospinal Fluid Biomarkers in AD 219 Conclusion 219 Background 219 Search strategy 220 Selection criteria 220 Analytical principles for CSF T-tau, P-tau and Aß42 221 CSF total tau (T-tau) 221 CSF ß-amyloid (Aß42) 222 CSF phosphorylated tau (P-tau) 222 Diagnostic performance of CSF markers for AD 223 CSF T-tau 223 Aß42 224 CSF P-tau 224 Combination of CSF markers 224 CFS markers in early Alzheimer’s disease and MCI 225 CFS markers in other cognitive, psychiatric 226 and neurological disorders References 276 21. Interventions in Dementia Disorders 285 Background 285 Questions of interest 286 Study quality and levels of evidence 287 Methodological aspects of pharmacological studies 288 Selection and setting 288 Which patients were included in the efficacy analyses: 289 ITT, ITT-LOCF or OC? Long-term effects 290 Concepts of care 291 Quality of life 292 References 293 22. Pharmacological Treatment of Dementia – 295 Established Drugs Conclusions 295 Adverse events 296 Other conclusions 296 Background 297 Acetylcholinesterase inhibitors (AChEIs) 297 Memantine 298 Aim 298 Methods 298 Strategy for searching the literature 298 Included trials: Acetylcholinesterase inhibitors in AD 299 Donepezil 299 Rivastigmine 300 Galantamine 300 Included trials: Memantine 300 Measurements of efficacy 301 Global function 301 Cognitive function 302 ADL 303 Behavioral disturbances and psychological symptoms 303 Measurements of acceptability and safety 303 Acetylcholinesterase inhibitors in AD 304 Presentation of results 304 Effects on global function, primary outcomes: 304 CIBIC+ and GBS Effects on global function, secondary outcomes 305 Effects on cognitive function, primary outcomes: 305 ADAS-cog Effects on cognitive function: secondary outcomes 306 Effects on ADL 307 Effects on BPSD 308 Moderate to severe dementia 308 Acceptability and tolerability 309 Results after short-term treatment, effects 311 of washout and placebo effects Prediction of response 311 Neuroimaging findings in RCTs 312 Comparisons among different acetylcholinesterase 313 inhibitors Memantine in AD and VaD 313 Global function 313 Cognitive function 314 ADL function and BPSD 314 Acceptability and tolerability 314 Combined memantine and donepezil treatment 315 Acetylcholinesterase inhibitors in VaD 315 Results for donepezil 315 Results for galantamine 317 Other neurodegenerative dementia disorders 317 Cholinesterase inhibitors in dementia with Lewy bodies 317 (DLB) Cholinesterase inhibitors in Parkinson’s disease (PD) 318 and dementia Frontotemporal dementia (FTD) 318 Cholinesterase inhibitors in Down syndrome 319 Need for research 319 References 354 23. Hypertension and Dementia 361 Conclusions 361 Background 361 Search of literature 361 Results 362 Need for research 363 References 364 24. Treatment of Depression in Dementia 365 Conclusions 365 Background 365 Search strategy 366 Search results 366 Effects of antidepressants on depression in dementia 367 Effects of antidepressants on non-depressive symptoms 368 References 378 25. Treatment of Psychotic and Behavioral Symptoms 381 in Dementia Conclusions 381 Background 382 Effects of antipsychotic treatment of psychotic 383 symptoms and BPSD Search 383 Results 383 Study on withdrawal of antipsychotic 386 treatment in dementia Treatment of BPSD with antidepressants 386 Rate of decline of cognitive symptoms 387 during antipsychotic treatment Effects of antipsychotics on cerebral 387