Appendix 1. Protocol

Do Statins Impair Cognition? Protocol for a Systematic Review and Meta-Analysis of Randomized Controlled Trials

Brian R. Ott, MD, Lori A. Daiello, PharmD, ScM, Issa J. Dahabreh, MD, MSBeth A. Springate, PhD, Kimberly Bixby, BS, Manjari Murali, PhD, Thomas A. Trikalinos, MD

Background and Significance

The basis for disagreement between reports of clinically significant adverse effects of statins on cognition and the accumulated evidence from RCTs remains unclear. To address this conundrum, we will perform a systematic review and meta-analysis (when possible) of cognitive test results and adverse event reports from randomized controlled trials (RCTs) of statin treatment in two major groups of subjects: 1) cognitively normal older adults, and 2) persons with dementia or other forms of cognitive impairment.

Review Question(s)

1) To determine the effects of statins on cognitive function in two groups: adults with normal cognition, and those with dementia or other type of cognitive impairment.

2) To determine whether blood-brain barrier penetrability differentiates among statins more likely to be associated with adverse cognitive effects

Searches

The literature search strategy will include four components: 1) a search for statin RCTs identified in three previous Cochrane reviews that examined cognitive outcomes for the prevention 23 and treatment of dementia,24 and another that examined statins for the primary prevention of cardiovascular outcomes.25 This strategy will capture statin RCTs published through 2008; 2) a search of the Cochrane Central registry of trials and the MEDLINE, EMBASE databases for RCTs of statins with neurocognitive outcomes through 2008 to identify trials that those Cochrane reviews may have excluded; 3) an additional search of these databases to identify statin RCTs, irrespective of outcomes, between 2008 and December 2012; and 4) and a search for additional statin RCTs from a network meta-analysis of statins and adverse effects.26

Types of studies to be included

All RCTs of statins approved for use in the U.S. or Europe (simvastatin, rosuvastatin, atorvastatin, fluvastatin, pravastatin, lovastatin, mevastatin, cerivastatin, pitavastatin) with or without other lipid lowering agents. Trials of statins performed in humans, published in English, mean number of participants per arm >10, and with any duration of follow-up.

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Condition or domain being studied

Cognitive impairment, regardless of diagnosis, that is measured by validated rating scales.

Participants/ population

No studies will be excluded based on patient characteristics.

Intervention(s), exposure(s)

RCTs comparing statin therapy with or without other lipid lowering agents, versus no statins.

Comparator(s)/ control

Placebo

Outcome(s)

Primary outcomeMeasures of overall cognitive functioning from global cognitive scales, neuropsychological test performance in individual cognitive domains (executive function, attention, processing speed, memory, working memory), or global measures constructed by combining cognitive domain scores. Dichotomous classifications of cognitive impairment (e.g., dementia vs. no dementia).

Secondary outcomeIncidence of cognitive-related, treatment emergent adverse events (e.g. memory loss, forgetfulness, amnesia, memory impairment, and confusion), by statin lipophilicity.

Data extraction, (selection and coding)

A pilot round of the same 300 abstracts using Abstrackr software will be conducted with all authors to ensure accuracy during the screening stage.27 Papers that are selected in the abstract screening phase will be retrieved and examined in full text for eligibility. Two reviewers will read the studies to determine the final study selection. Disagreements will be evaluated by one of the principal investigators (BO or LD) and discrepancies resolved with the involvement of a third reviewer (TT or ID) when necessary.

The data will then be extracted by one author, and verified by another. To ensure accuracy, one reviewer will record the information using the data abstraction form, and another will independently verify the results. The analysis dataset will be made available via the Systematic Review Data Repository (SRDR).25

Data to extract

Participant characteristics, study characteristics including objectives, year of publication, sample size, setting, country, funding mechanism, duration of follow up, randomization method,

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reporting of dropouts, intervention and comparator details, and cognitive outcomes and harms. For categorical outcomes we will extract the number experiencing the outcome in each arm. For continuous outcomes, test scores to calculate the mean differences at end of follow-up will be extracted. Differences in net changes (i.e., final minus baseline values between groups) will be extracted only when mean differences of final values are unavailable.28

Risk of bias (quality) assessmentThe presence or absence of bias will be assessed with methodological items that correspond to those included in the Cochrane Risk of Bias tool29 (adequacy of random sequence generation, allocation concealment, blinding to treatment assignment, completeness of follow-up data (defined as loss to follow-up and treatment discontinuation rates lower than 20%), and lack of differential loss to follow-up or treatment discontinuation (defined as Fisher’s exact p-value >0.05 or difference in absolute rates <5%, across study groups)) and will be entered into SRDR. Two independent reviewers will rate risk of bias as high, low, or unclear for each item and discrepancies will be resolved by consensus. Meta-regression weighted least squares analyses will be performed for risk of bias item when items are variable across studies, and 6 or more studies are available for the analysis.

Strategy for data synthesis

Results of the systematic review will be described narratively. Meta-analyses will be performed with random effects models fit with weighted least-squares methods when information from two or more RCTs is available. Separate meta-analyses will be performed for RCTs in cognitively normal subjects, and in patients with dementia or other types of cognitive impairment. Continuous outcomes reported on the same scale (e.g., ADAS-Cog,30 MMSE31) will be considered as weighted mean differences at study endpoint. For continuous outcomes reported on different scales will be summarized as standardized mean differences (SMDs), using the Hedges g metric and the robust variance estimator.34,32. P-values and 95% confidence intervals will be calculated for effect estimates. Between-study heterogeneity will be assessed using the estimated between-study standard deviation (e.g., τ, the square root of the between-study variance).

Subgroup analyses

Random effects meta-regression with weighted least squares will be utilized to investigate the contribution of degree of blood brain barrier penetrability to between-study differences for cognitive effects, categorizing statins according to higher vs. lower propensity to cross the blood-brain barrier.35

Summary

By performing the systematic review and applying meta-analytic methods(where appropriate) to analyze both neuropsychological test change scores and discrete adverse event reports, we hope to advance the understanding of the association between statins and adverse cognitive effects that warrant discontinuation of the medication. This is a question with major public health implications due to 1) the increasingly high prevalence of statin use in the U.S. and the world,

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and 2) the known health benefits of statin therapy in the primary and secondary prevention of cardiovascular and cerebrovascular death and morbidity.

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Appendix 2. Systematic review literature search strategy

A. Strategy for randomized clinical trials in non-dementia patients

CENTRAL on The Cochrane Library

1. MeSH descriptor Hydroxymethylglutaryl-CoA Reductase Inhibitors explode all trees 2. statin or statins 3. atorvastatin 4. cerivastatin 5. fluvastatin 6. lovastatin 7. pravastatin 8. simvastatin 9. pitavastatin10. lipitor 11. baycol 12. lescol 13. mevacor 14. altocor 15. pravachol 16. lipostat 17. zocor 18. rosuvastatin19. Livalo20. (hydroxymethylglutaryl next coenzyme next reductase next inhibitor) 21. (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9) 22. (#10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19) 23. (#21 or #22)

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MEDLINE on Ovid1. exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/ 2. (statin or statins).tw. 3. atorvastatin.tw. 4. cerivastatin.tw. 5. fluvastatin.tw. 6. lovastatin.tw. 7. pravastatin.tw. 8. simvastatin.tw. 9. pitavastatin.tw.10. lipitor.tw. 11. baycol.tw. 12. lescol.tw. 13. mevacor.tw. 14. altocor.tw. 15. pravachol.tw. 16. lipostat.tw. 17. zocor.tw. 18. mevinolin.tw. 19. compactin.tw. 20. fluindostatin.tw. 21. rosuvastatin.tw.22. livalo.tw. 23. or/1-22 24. exp Cardiovascular Diseases/ 25. cardiovascular.tw. 26. heart disease$.tw. 27. coronary disease$.tw. 28. angina.tw. 29. heart failure.tw. 30. cardiac failure.tw. 31. exp Hyperlipidemia/ 32. hyperlipid$.tw. 33. hypercholesterol$.tw. 34. exp Cholesterol/ 35. cholesterol$.tw. 36. randomized controlled trial.pt. 37. controlled clinical trial.pt. 38. Randomized controlled trials/ 39. random allocation.sh. 40. double blind method.sh. 41. single-blind method.sh. 42. or/36-41 43. exp animal/ not human/ 44. 42 not 4345. clinical trial.pt.

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46. exp Clinical trials/ 47. (clin$ adj25 trial$).ti,ab. 48. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab. 49. placebos.sh. 50. placebo$.ti,ab. 51. random$.ti,ab. 52. research design.sh. 53. or/45-52 54. 53 not 43 55. 44 or 54 56. or/24-35 57. 23 and 56 and 55

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MEDLINE on Ovid (randomized trial terms omitted)1. exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/ 2. (statin or statins).tw. 3. atorvastatin.tw. 4. cerivastatin.tw. 5. fluvastatin.tw. 6. lovastatin.tw. 7. pravastatin.tw. 8. simvastatin.tw. 9. pitavastatin.tw.10. lipitor.tw. 11. baycol.tw. 12. lescol.tw. 13. mevacor.tw. 14. altocor.tw. 15. pravachol.tw. 16. lipostat.tw. 17. zocor.tw. 18. mevinolin.tw. 19. compactin.tw. 20. fluindostatin.tw. 21. rosuvastatin.tw.22. livalo.tw. 23. or/1-22 24. exp Cardiovascular Diseases/ 25. cardiovascular.tw. 26. heart disease$.tw. 27. coronary disease$.tw. 28. angina.tw. 29. heart failure.tw. 30. cardiac failure.tw. 31. exp Hyperlipidemia/ 32. hyperlipid$.tw. 33. hypercholesterol$.tw. 34. exp Cholesterol/ 35. cholesterol$.tw. 36. randomized controlled trial.pt. 37. controlled clinical trial.pt. 38. Randomized controlled trials/ 39. random allocation.sh. 40. double blind method.sh. 41. single-blind method.sh. 42. or/24-35 43. exp animal/ not human/ 44. 42 not 4345. 23 and 44

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EMBASE on Ovid 1. exp Hydroxymethylglutaryl Coenzyme Reductase Inhibitor/ 2. (statin or statins).tw. 3. atorvastatin.tw. 4. cerivastatin.tw. 5. fluvastatin.tw. 6. lovastatin.tw. 7. pravastatin.tw. 8. simvastatin.tw.9. pitavastatin.tw.10. lipitor.tw. 11. baycol.tw. 12. lescol.tw. 13. mevacor.tw. 14. altocor.tw. 15. pravachol.tw. 16. lipostat.tw. 17. zocor.tw. 18. mevinolin.tw. 19. compactin.tw. 20. fluindostatin.tw. 21. rosuvastatin.tw.22. livalo.tw. 23. or/1-22 24. exp Cardiovascular Disease/ 25. cardiovascular.tw. 26. heart disease$.tw. 27. coronary disease$.tw. 28. angina.tw. 29. heart failure.tw. 30. cardiac failure.tw. 31. exp Hyperlipidemia/ 32. hyperlipid$.tw. 33. hypercholesterol$.tw. 34. exp Cholesterol/ 35. cholesterol$.tw. 36. exp lipid blood level/ 37. or/24-36 38. 23 and 37 39. random$.ti,ab. 40. factorial$.ti,ab. 41. (crossover$ or cross over$ or cross-over$).ti,ab. 42. placebo$.ti,ab. 43. (double$ adj blind$).ti,ab. 44. (singl$ adj blind$).ti,ab. 45. assign$.ti,ab.

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46. allocat$.ti,ab. 47. volunteer$.ti,ab. 48. Crossover Procedure/ 49. Double Blind Procedure/ 50. Randomized Controlled Trial/ 51. Single Blind Procedure/ 52. or/39-5153. exp animal/ 54. nonhuman/ 55. exp animal experiment/ 56. or/53-55 57. exp human/ 58. 56 not 57 59. 52 not 58 60. 38 and 59

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EMBASE on Ovid (randomized trial terms omitted)1. exp Hydroxymethylglutaryl Coenzyme Reductase Inhibitor/ 2. (statin or statins).tw. 3. atorvastatin.tw. 4. cerivastatin.tw. 5. fluvastatin.tw. 6. lovastatin.tw. 7. pravastatin.tw. 8. simvastatin.tw.9. pitavastatin.tw.10. lipitor.tw. 11. baycol.tw. 12. lescol.tw. 13. mevacor.tw. 14. altocor.tw. 15. pravachol.tw. 16. lipostat.tw. 17. zocor.tw. 18. mevinolin.tw. 19. compactin.tw. 20. fluindostatin.tw. 21. rosuvastatin.tw.22. livalo.tw. 23. or/1-22 24. exp Cardiovascular Disease/ 25. cardiovascular.tw. 26. heart disease$.tw. 27. coronary disease$.tw. 28. angina.tw. 29. heart failure.tw. 30. cardiac failure.tw. 31. exp Hyperlipidemia/ 32. hyperlipid$.tw. 33. hypercholesterol$.tw. 34. exp Cholesterol/ 35. cholesterol$.tw. 36. exp lipid blood level/ 37. or/24-36 38. 23 and 37 39. exp animal/ 40. nonhuman/ 41. exp animal experiment/ 42. or/39-41 43. exp human/ 44. 42 not 43 45. 38 and 44

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B. Strategy for randomized clinical trials in dementia patients

The Cochrane Library1. statin*.tiabkw. 2. hydroxymethylglutaryl-CoA Reductase Inhibitors/ (all subheadings) 3. 1 OR 2 4. Alzheimer-disease/ all subheadings 5. exp dementia-vascular/ all subheadings 6. creutzfeldt-jakob-syndrome/ all subheadings 7. kluver-bucy-syndrome/ all subheadings 8. lewy-body-disease/ all subheadings 9. pick-disease-of-the-brain/ all subheadings 10. Huntington-disease/ all subheadings 11. delirium/ all subheadings 12. wernicke-encephalopathy/ all subheadings13. mild-cognitive-impairment/all subheadings 14. (dement$ OR Alzheimer$).tiab. 15. (lewy$ AND bod$).tiab. 16. ((cognit$ OR memor$ OR mental) and (decline$ OR impair$ OR los$ OR deteriorate$)).tiab. 17. (chronic AND cerebrovascular).tiab. 18. ((organic brain syndrome) OR (organic brain disease)).tiab. 19. ((cerebr$ AND deteriorate$) OR (cerebr$ AND insufficien$)).tiab. 20. ((pick$ and disease) or (creutzfeldt or JCD or CJD) or huntington$ or binswanger$ or korsako$).tiab. 21. 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 2022. 21 AND 4 23. limit 22 to (randomized controlled trial).pt.

NOTE: Run with and without item 23

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Medline (Ovid SP) – Randomized trials1. (statin$ OR lipophilic OR hydrophilic).mp. 2. (lovastatin OR simvastatin OR cervistatin OR atorvastatin OR rosuvastatin OR pravastatin OR fluvastatin OR pitavastatin).mp. 3. Hydroxymethylglutaryl-CoA Reductase Inhibitors/ all subheadings 4. Alzheimer-disease/ all subheadings 5. exp dementia-vascular/ all subheadings 6. creutzfeldt-jakob-syndrome/ all subheadings 7. kluver-bucy-syndrome/ all subheadings 8. lewy-body-disease/ all subheadings 9. pick-disease-of-the-brain/ all subheadings 10. Huntington-disease/ all subheadings 11. delirium/ all subheading 12. wernicke-encephalopathy/ all subheadings13. mild-cognitive-impairment/ all subheadings 14. (dement$ OR Alzheimer$).mp. 15. (lewy$ AND bod$).mp. 16. ((cognit$ OR memor$ OR mental) and (decline$ OR impair$ OR los$ OR deteriorate$)).mp. 17. (chronic AND cerebrovascular).mp. 18. ((organic brain syndrome) OR (organic brain disease)).mp. 19. ((cerebr$ AND deteriorate$) OR (cerebr$ AND insufficien$)).mp. 20. ((pick$ and disease) or (creutzfeldt or JCD or CJD) or huntington$ or binswanger$ or korsako$).mp. 21. 1 OR 2 OR 3 22. 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 2023. 21 AND 22 24. randomized controlled trial.pt. 25. controlled clinical trial.pt. 26. randomized.ab. 27. placebo.ab. 28. drug therapy.fs. 29. randomly.ab. 30. trial.ab. 31. groups.ab. 32. 24 OR 25 OR 26 OR 27 OR 28 OR 29 OR 30 OR 31 33. humans.sh.34. 32 AND 3335. 23 AND 34

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Medline (Ovid SP) – Without Randomized trials1. (statin$ OR lipophilic OR hydrophilic).mp. 2. (lovastatin OR simvastatin OR cervistatin OR atorvastatin OR rosuvastatin OR pravastatin OR fluvastatin OR pitavastatin).mp. 3. Hydroxymethylglutaryl-CoA Reductase Inhibitors/ all subheadings 4. Alzheimer-disease/ all subheadings 5. exp dementia-vascular/ all subheadings 6. creutzfeldt-jakob-syndrome/ all subheadings 7. kluver-bucy-syndrome/ all subheadings 8. lewy-body-disease/ all subheadings 9. pick-disease-of-the-brain/ all subheadings 10. Huntington-disease/ all subheadings 11. delirium/ all subheading 12. wernicke-encephalopathy/ all subheadings13. mild-cognitive-impairment/ all subheadings 14. (dement$ OR Alzheimer$).mp. 15. (lewy$ AND bod$).mp. 16. ((cognit$ OR memor$ OR mental) and (decline$ OR impair$ OR los$ OR deteriorate$)).mp. 17. (chronic AND cerebrovascular).mp. 18. ((organic brain syndrome) OR (organic brain disease)).mp. 19. ((cerebr$ AND deteriorate$) OR (cerebr$ AND insufficien$)).mp. 20. ((pick$ and disease) or (creutzfeldt or JCD or CJD) or huntington$ or binswanger$ or korsako$).mp. 21. 1 OR 2 OR 3 22. 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 2023. 21 AND 22 24. humans.sh. 25. 23 AND 24

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Embase (Ovid SP) – Randomized trials1. (statin$ OR lipophilic OR hydrophilic).mp. 2. (lovastatin OR simvastatin OR cervistatin OR atorvastatin OR rosuvastatin OR pravastatin OR fluvastatin OR pitavastatin).mp. 3. Hydroxymethylglutaryl-CoA Reductase Inhibitors/ all subheadings 4. Alzheimer-disease/ all subheadings 5. exp dementia-vascular/ all subheadings 6. creutzfeldt-jakob-syndrome/ all subheadings 7. kluver-bucy-syndrome/ all subheadings 8. lewy-body/ all subheadings 9. pick-presenile-dementia/ all subheadings 10. Huntington-chorea/ all subheadings 11. delirium/ all subheading 12. wernicke-encephalopathy/ all subheadings13. mild-cognitive-impairment/ all subheadings 14. (dement$ OR Alzheimer$).mp. 15. (lewy$ AND bod$).mp. 16. ((cognit$ OR memor$ OR mental) and (decline$ OR impair$ OR los$ OR deteriorate$)).mp. 17. (chronic AND cerebrovascular).mp. 18. ((organic brain syndrome) OR (organic brain disease)).mp. 19. ((cerebr$ AND deteriorate$) OR (cerebr$ AND insufficien$)).mp. 20. ((pick$ and disease) or (creutzfeldt or JCD or CJD) or huntington$ or binswanger$ or korsako$).mp. 21. 1 OR 2 OR 3 22. 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 23. 21 AND 22 24. randomized controlled trial.pt. 25. controlled clinical trial.pt. 26. randomized.ab. 27. placebo.ab. 28. drug therapy.fs. 29. randomly.ab. 30. trial.ab. 31. groups.ab. 32. 24 OR 25 OR 26 OR 27 OR 28 OR 29 OR 30 OR 31 33. humans.sh. 34. 32 AND 3335. 23 AND 33

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Embase (Ovid SP) – Without Randomized trials1. (statin$ OR lipophilic OR hydrophilic).mp. 2. (lovastatin OR simvastatin OR cervistatin OR atorvastatin OR rosuvastatin OR pravastatin OR fluvastatin OR pitavastatin).mp. 3. Hydroxymethylglutaryl-CoA Reductase Inhibitors/ all subheadings 4. Alzheimer-disease/ all subheadings 5. exp dementia-vascular/ all subheadings 6. creutzfeldt-jakob-syndrome/ all subheadings 7. kluver-bucy-syndrome/ all subheadings 8. lewy-body/ all subheadings 9. pick-presenile-dementia/ all subheadings 10. Huntington-chorea/ all subheadings 11. delirium/ all subheading 12. wernicke-encephalopathy/ all subheadings13. mild-cognitive-impairment/ all subheadings 14. (dement$ OR Alzheimer$).mp. 15. (lewy$ AND bod$).mp. 16. ((cognit$ OR memor$ OR mental) and (decline$ OR impair$ OR los$ OR deteriorate$)).mp. 17. (chronic AND cerebrovascular).mp. 18. ((organic brain syndrome) OR (organic brain disease)).mp. 19. ((cerebr$ AND deteriorate$) OR (cerebr$ AND insufficien$)).mp. 20. ((pick$ and disease) or (creutzfeldt or JCD or CJD) or huntington$ or binswanger$ or korsako$).mp. 21. 1 OR 2 OR 3 22. 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 23. 21 AND 22 24. humans.sh. 25. 23 AND 24

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Appendix 3. Cognitive tests used in the included studies.

Author, year Cognitive tests (data were not analyzable from all tests in each study)Berk-Planken, 2002 (DALI) CVLT (verbal memory test)Carlsson, 2008 CVLT-II Long Delay Free Recall

Paragraph Delayed RecallVisual Spatial Learning Test Delayed RecallVisual Reproduction II Delayed RecallLetter FluencyComplex Figure CopyGrooved Peg Board (time, sec)Bells Visual Neglect Test (time, sec)Symbol SearchMental Control 1 to 20 (time, sec)Mental Control 20 to 1 (time, sec)Stroop Color-Word ScoreTrailmaking Test B

Carlsson, 2002 Digit Symbol Substitution Score (Wechsler Adult Intelligence Scale-R)Santanello, 1997 CRISP Digit Symbol Substitution Score (Wechsler Adult Intelligence Scale-R)Cutler, 1995 Digit Symbol Substitution (number correct)

Choice Reaction Time (hit reaction time, sec)Choice Reaction Time (number of hits)Choice Reaction Time (number of false alarms)Auditory Vigilance (number of errors)Word Recall Trial 1 (number of words)Word Recall Trial 4 (number of words)Finger Tapping (number of taps)Visual Analogue Scale (alert-drowsy score, mm)Visual Analogue Scale (factor 1, alertness score)Profile of Mood States (vigor/activity)Profile of Mood States (fatigue/inertia)Profile of Mood States (confusion/bewilderment)

Gengo, 1995 Digit Symbol Substitution (number correct)Choice Reaction Time (recognition time, sec)Choice Reaction Time (total reaction time)Auditory Vigilance (number of errors)Word Recall Trial 1 (number of words)Word Recall Trial 4 (number of words)Finger Tapping (number of taps)Visual Analogue Scale (alert-drowsy score, mm)Visual Analogue Scale (factor 1, alertness score)Profile of Mood States (vigor/activity)Profile of Mood States (fatigue/inertia)Profile of Mood States (confusion/bewilderment)

Gibellato, 2001 Vigilance test (mean response time, HITRT)Vigilance test (d', perceptual sensitivity, DPRIME)Visual Sequence Comparison Test (VSCPUT)Symbol Digit Coding (SDCPUT)Divided Attention Test (DATIRTC)

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Divided Attention Test (DATDRTC)Auditory Sequence Comparison Test (ASCPUT)PFNPUTShifting Attention Test (SATDIPUT)Dual Task Tracking (DTTPAPUT)Dual Task Tracking (DTTPDPUT)

Harrison, 1994 Digit Symbol Substitution Test (DSST)Kostis, 1994 Visual reaction time (sec)

Auditory Reaction Time (sec)Rey Verbal LearningEmbedded Figures TestVerbal Fluency TestTrailmaking Test ATrailmaking Test BVisual Memory Test

Krab, 2008 Rey Complex Figure Test (delayed recall)Cancellation Test (speed)Cancellation Test (standard deviation, raw score)Stroop (speed)Block DesignObject AssemblyRey Complex Figure Test (copy)Beery Visual Motor IntegrationJudgement of Line Orientation Test

Sparks, 2005 (ADCLT) ADAS-CogMini-Mental State Examination (MMSE)

Feldman, 2010 (LEADe) ADAS-CogClinical Dementia Rating-Sum of Boxes (CDR-SB)Mini-Mental State Examination (MMSE) Modified Alzheimer’s Disease Assessment Scale-Cognitive Subscale (Mod ADAS-COG)

Shepherd, 2010 (PROSPER) letter digit codes (number correct)picture word learning test (number remembered)Stroop test (sec)Mini-Mental State Examination (MMSE)

Tendolkar, 2011 Auditory Verbal Learning Test delayed recall Auditory Verbal Learning Test immediate recall Digit symbol substitution testMMSE

Tapia-Perez, 2008 Galveston orientation amnesia test @120daysSummers, 2007 (LORD) 100-item Stroop color Word test

Digit symbol coding (of Wechsler Adult Intelligence Scale -3)Trail Making Test

Simmons, 2002 MMSEADAS-cog

Sano, 2011 (ADCS) ADAS-cog MMSE (change)Maze A2 (executive function)Number cancellation (visual attention)

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Delayed Word Recall Sanchez-Aguilar, 2013 Galveston orientation amnesia test @120daysRoth, 1992 Simple reaction time (ms)

Choice reaction time (ms) Divided attention - GLOBAL (arbitrary units)Vigilance - GLOBAL (arbitrary units)Divided attention - central response time (ms) Divided attention - peripheral response time (ms) Divided attention - tracking errorVigilance - reaction time (ms) Vigilance - missed stimuli

Muldoon, 2000 Digit Vigilance (attention & mental flexibility) - errorsRecurring Words (attention)Elithorn maze (psychomotor speed) Grooved Pegboard (psychomotor speed) Letter Rotation (attention & mental flexibility) Digit Span (attention & working memory)Digit symbol (psychomotro speed) Stroop interference (mental flexibility) Trail making (mental flexibility) Associative learning (working memory) controlled oral work association (memory retrieval)digit symbol recall (memory retrieval) verbal recall (memory retrieval) complex figure (memory retrieval)

Muldoon, 2004 Digit Vigilance (attention & mental flexibility) - errorsRecurring Words (attention) - % correctElithorn maze (psychomotor speed) - secGrooved Pegboard (psychomotor speed) - secMinor tracing - errors4-Word memory - num correctLetter Rotation (attention & mental flexibility) Digit Span (attention & working memory)Digit symbol (psychomotro speed) Stroop interference (mental flexibility) Trail making (mental flexibility) complex figure (memory retrieval)

HPS Collaborative Group, 2004 Telephone Interview for Cognitive StatusTelephone Interview for Cognitive Status - Memory componentTelephone Interview for Cognitive Status - Verbal fluency

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