# Supplemental Evidence and Data Request on Diagnostic and Treatment of Clinical Alzheimer's-Type Dementia (CATD)
**AGENCY:**
Agency for Healthcare Research and Quality (AHRQ), HHS.
**ACTION:**
Request for supplemental evidence and data submissions.
**SUMMARY:**
The Agency for Healthcare Research and Quality (AHRQ) is seeking scientific information submissions from the public. Scientific information is being solicited to inform our review of *Diagnostic and Treatment of Clinical Alzheimer's-type Dementia (CATD),* which is currently being conducted by the AHRQ's Evidence-based Practice Centers (EPC) Program. Access to published and unpublished pertinent scientific information will improve the quality of this review.
**DATES:**
*Submission Deadline* on or before January 17, 2019.
**ADDRESSES:**
*Email submissions: [email protected].*
*Print submissions:*
*Mailing Address:* Center for Evidence and Practice Improvement, Agency for Healthcare Research and Quality, ATTN: EPC SEADs Coordinator, 5600 Fishers Lane, Mail Stop 06E53A, Rockville, MD 20857.
*Shipping Address (FedEx, UPS, etc.):* Center for Evidence and Practice Improvement, Agency for Healthcare Research and Quality, ATTN: EPC SEADs Coordinator, 5600 Fishers Lane, Mail Stop 06E77D, Rockville, MD 20857.
**FOR FURTHER INFORMATION CONTACT:**
Jenae Benns, Telephone: 301-427-1496 or Email: *[email protected].*
**SUPPLEMENTARY INFORMATION:**
The Agency for Healthcare Research and Quality has commissioned the Evidence-based Practice Centers (EPC) Program to complete a review of the evidence for *Diagnostic and Treatment of Clinical Alzheimer's-type Dementia (CATD).* AHRQ is conducting this systematic review pursuant to Section 902(a) of the Public Health Service Act, 42 U.S.C. 299a(a).
The EPC Program is dedicated to identifying as many studies as possible that are relevant to the questions for each of its reviews. In order to do so, we are supplementing the usual manual and electronic database searches of the literature by requesting information from the public ( *e.g.,* details of studies conducted). We are looking for studies that report on *Diagnostic and Treatment of Clinical Alzheimer's-type Dementia (CATD),* including those that describe adverse events. The entire research protocol, including the key questions, is also available online at: *https://effectivehealthcare.ahrq.gov/topics/alzheimers-type-dementia/protocol.*
This is to notify the public that the EPC Program would find the following information on *Diagnostic and Treatment of Clinical Alzheimer's-type Dementia (CATD)* helpful:
A list of completed studies that your organization has sponsored for this indication. In the list, please *indicate whether results are available on ClinicalTrials.gov along with the ClinicalTrials.gov trial number.*
*For completed studies that do not have results on ClinicalTrials.gov,* please provide a summary, including the following elements: study number, study period, design, methodology, indication and diagnosis, proper use instructions, inclusion and exclusion criteria, primary and secondary outcomes, baseline characteristics, number of patients screened/eligible/enrolled/lost to follow-up/withdrawn/analyzed, effectiveness/efficacy, and safety results.
*A list of ongoing studies that your organization has sponsored for this indication.* In the list, please provide the *ClinicalTrials.gov* trial number or, if the trial is not registered, the protocol for the study including a study number, the study period, design, methodology, indication and diagnosis, proper use instructions, inclusion and exclusion criteria, and primary and secondary outcomes.
Description of whether the above studies constitute ALL Phase II and above clinical trials sponsored by your organization for this indication and an index outlining the relevant information in each submitted file.
Your contribution will be very beneficial to the EPC Program. Materials submitted must be publicly available or able to be made public. Materials that are considered confidential; marketing materials; study types not included in the review; or information on indications not included in the review cannot be used by the EPC Program. This is a voluntary request for information, and all costs for complying with this request must be borne by the submitter.
The draft of this review will be posted on AHRQ's EPC Program website and available for public comment for a period of 4 weeks. If you would like to be notified when the draft is posted, please sign up for the email list at: *https://www.effectivehealthcare.ahrq.gov/email-updates.*
The systematic review will answer the following questions. This information is provided as background. AHRQ is not requesting that the public provide answers to these questions.
**The Key Questions**
*KQ 1:* In adults with CATD, what are the efficacy and harms of prescription pharmacological interventions versus placebo/inactive control for treatment of cognition, function, and quality of life?
*KQ 1a:* In adults with CATD, does the efficacy of prescription pharmacological interventions versus placebo/inactive control vary as a function of patient characteristics ( *i.e.,* age, sex, race/ethnicity, depression, pre-treatment cognitive or functional level/CATD stage, living setting)?
*KQ 2:* In adults with CATD, what are the efficacy and harms of nonprescription pharmacological interventions versus placebo/inactive control for treatment of cognition, function, and quality of life?
*KQ 2a:* In adults with CATD, does the efficacy of nonprescription pharmacological interventions versus placebo/inactive control vary as a function of patient characteristics ( *i.e.,* age, sex, race/ethnicity, depression, pre-treatment cognitive or functional level/CATD stage, living setting)?
*KQ 3:* In adults with CATD, what are the comparative effectiveness and harms of prescription pharmacological interventions versus other active interventions for treatment of cognition, function, and quality of life?
*KQ 3a:* In adults with CATD, what are the comparative effectiveness and harms of prescription pharmacological interventions versus other prescription pharmacological interventions for treatment of cognition, function, and quality of life?
*KQ 3b:* In adults with CATD, what are the comparative effectiveness and harms of prescription pharmacological interventions versus nonprescription pharmacological interventions for treatment of cognition, function, and quality of life?
*KQ 3c:* In adults with CATD, what are the comparative effectiveness and harms of prescription pharmacological interventions versus nonpharmacological interventions for treatment of cognition, function, and quality of life?
*KQ 3d:* In adults with CATD, does the comparative effectiveness of prescription pharmacological interventions versus other active interventions for treatment of cognition, function, and quality of life vary as a function of patient characteristics ( *i.e.,* age, sex, race/ethnicity, depression, pre-treatment cognitive or functional level/CATD stage, living setting)?
*KQ 4:* In adults with CATD and behavioral and psychological symptoms of dementia (BPSD), what are the efficacy and harms of prescription pharmacological interventions versus placebo/inactive control for treatment of BPSD?
*KQ 4a:* In adults with CATD and BPSD, what are the efficacy and harms of prescription pharmacological interventions versus placebo/inactive control for reducing frequency and severity of future BPSD?
*KQ 4b:* In adults with CATD and BPSD, does the efficacy of prescription pharmacological interventions versus placebo/inactive control for reducing frequency and severity of future BPSD vary as a function of patient characteristics ( *i.e.,* age, sex, race/ethnicity, depression, pre-treatment cognitive or functional level/CATD stage, pre-treatment BPSD severity, living setting)?
*KQ 4c:* In adults with CATD and BPSD, what are the efficacy and harms of prescription pharmacological interventions versus placebo/inactive control for acute treatment of BPSD?
*KQ 4d:* In adults with CATD and BPSD, does the efficacy of prescription pharmacological interventions versus placebo/inactive control for acute treatment of BPSD vary as a function of patient characteristics ( *i.e.,* age, sex, race/ethnicity, depression, pre-treatment cognitive or functional level/CATD stage, pre-treatment BPSD severity, living setting)?
*KQ 5:* In adults with CATD and BPSD, what are the efficacy and harms of nonprescription pharmacological interventions versus placebo/inactive control for treatment of BPSD in adults with CATD and BPSD?
*KQ 5a:* In adults with CATD and BPSD, what are the efficacy and harms of nonprescription pharmacological interventions versus placebo/inactive control for reducing frequency and severity of future BPSD?
*KQ 5b:* In adults with CATD and BPSD, does the efficacy of nonprescription pharmacological interventions versus placebo/inactive control for reducing frequency and severity of future BPSD vary as a function of patient characteristics ( *i.e.,* age, sex, race/ethnicity, depression, pre-treatment cognitive or functional level/CATD stage, pre-treatment BPSD severity, living setting)?
*KQ 5c:* In adults with CATD and BPSD, what are the efficacy and harms of nonprescription pharmacological interventions versus placebo/inactive control for acute treatment of BPSD?
*KQ 5d:* In adults with CATD and BPSD, does the efficacy of nonprescription pharmacological interventions versus placebo/inactive control for acute treatment of BPSD vary as a function of patient characteristics ( *i.e.,* age, sex, race/ethnicity, depression, pre-treatment cognitive or functional level/CATD stage, pre-treatment BPSD severity, living setting)?
*KQ 6:* In adults with CATD and BPSD, what are the comparative effectiveness and harms of prescription pharmacological interventions versus other active interventions for treatment of BPSD?
*KQ 6a:* In adults with CATD and BPSD, what are the comparative effectiveness and harms of prescription pharmacological interventions versus other prescription pharmacological interventions for reducing frequency and severity of future BPSD?
*KQ 6b:* In adults with CATD and BPSD, what are the comparative effectiveness and harms of prescription pharmacological interventions versus nonprescription pharmacological interventions for reducing frequency and severity of future BPSD?
*KQ 6c:* In adults with CATD and BPSD, what are the comparative effectiveness and harms of prescription pharmacological interventions versus nonpharmacological interventions for reducing frequency and severity of future BPSD?
*KQ 6d:* In adults with CATD and BPSD, does the comparative effectiveness of prescription pharmacological interventions versus other active interventions for reducing frequency and severity of future BPSD vary as a function of patient characteristics ( *i.e.,* age, sex, race/ethnicity, depression, pre-treatment cognitive or functional level/CATD stage, pre-treatment BPSD severity, living setting)?
*KQ 6e:* In adults with CATD and BPSD, what are the comparative effectiveness and harms of prescription pharmacological interventions versus other prescription pharmacological interventions for acute treatment of BPSD?
*KQ 6f:* In adults with CATD and BPSD, what are the comparative effectiveness and harms of prescription pharmacological interventions versus nonprescription pharmacological interventions for acute treatment of BPSD?
*KQ 6g:* In adults with CATD and BPSD, what are the comparative effectiveness and harms of prescription pharmacological interventions versus nonpharmacological interventions for acute treatment of BPSD?
*KQ 6h:* In adults with CATD and BPSD, does the comparative effectiveness of prescription pharmacological interventions versus other active interventions for acute treatment of BPSD vary as a function of patient characteristics ( *i.e.,* age, sex, race/ethnicity, depression, pre-treatment cognitive or functional level/CATD stage, pre-treatment BPSD severity, living setting)?
*KQ 7:* In adults with suspected CATD, what are the accuracy, comparative accuracy, and harms of different individual cognitive diagnostic tests and their combinations for making the diagnosis of CATD as defined by full clinical evaluation and/or neuropsychological testing with explicit diagnostic criteria?
*KQ 7a:* Do the accuracy and comparative accuracy of cognitive tests for making the diagnosis of CATD as defined by full clinical evaluation and/or neuropsychological testing with explicit diagnostic criteria vary as a function of patient characteristics ( *i.e.,* age, sex, race/ethnicity, education, pre-testing cognitive or functional level CATD stage)?
*KQ 8:* In adults with a clinical diagnosis of CATD, what are the accuracy, comparative accuracy, and harms of brain imaging, CSF, and blood tests for diagnosing pathologically confirmed Alzheimer's disease as the underlying etiology?
*KQ 8a:* Do the accuracy and comparative accuracy of brain imaging, CSF, and blood tests for pathologically confirmed Alzheimer's disease as the underlying etiology of CATD vary as a function of patient characteristics ( *i.e.,* age, sex, race/ethnicity, depression, education, pre-testing cognitive or functional level CATD stage)?
| KQ | Population | Intervention | Treatment comparator or diagnostic reference standard | Health outcomes & harms | Timing | Setting | Study design |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Drug treatment efficacy, comparative effectiveness & harms on cognition, function & quality of life | Adults with CATD ≥50 years of age | Cholinesterase inhibitors, NMDA antagonists | Placebo, Other inactive control | Change in patient cognition (global screen, multidomain, memory, executive function, language, attention), function, or QOL on validated test | ≥24 weeks | Community-dwelling, Assisted living | RCT, CCT, systematic review of RCTs or CCTs. |
| | | | | | | | |
| Drug treatment efficacy, comparative effectiveness & harms on BPSD | Adults with CATD ≥50 years of age with BPSD (studies specified BPSD inclusion criterion) | Cholinesterase inhibitors, NMDA antagonists, Antipsychotics, second generation (any) and first generation (only haloperidol), Antidepressants, Anti-seizure/mood stabilizers, Anxiolytics, benzodiazepine, Anxiolytics, other Hormonal agents (Disinhibited sexual behavior only), Cannabinoids, Combinations | Placebo, Other inactive control | | ≥2 weeks | Community-dwelling, Assisted living, Nursing home | RCT, CCT, systematic review of RCTs or CCTs. |
| | | | | Somnolence, Confusion/Delirium. | | | |
| Diagnostic test accuracy & harms (also see Table 2 below) | Adults ≥50 years of age with suspected CATD | Global (brief screens, multi-domain batteries), Single domain tests (memory, executive, language, attention | Full clinical evaluation and/or neuropsychological testing with explicit diagnostic criteria | | Any | Community-dwelling, Assisted living | Controlled observational studies (
cross-sectional, retrospective cohort, case control); systematic review of controlled observational studies. |
| Class of drug | Drug name(s) |
| --- | --- |
| Cholinesterase inhibitor | Donepezil *, rivastigmine *, galantamine *. |
| NMDA receptor antagonist | Memantine *. |
| Cholinesterase inhibitor/NMDA receptor antagonist combination | Donepezil/Memantine *. |
| 1st generation (typical) antipsychotic | only Haloperidol. |
| 2nd generation (atypical) antipsychotic | Risperidone, quetiapine, olanzapine, aripiprazole, clozapine. |
| Anti-depressant, selective serotonin-reuptake inhibitor (SSRI) | Citalopram, escitalopram, sertraline, fluoxetine, fluvoxamine, paroxetine. |
| Anti-depressant, serotonin-norepinephrine reuptake inhibitor (SNRI) | Duloxetine, venlafaxine. |
| Anti-depressant, other † | Trazodone, bupropion, mirtazapine. |
| Anti-seizure/mood stabilizer | Valproate, gabapentin, carbamazepine, lamotrigine. |
| Anti-anxiety, benzodiazepine | Clonazepam, diazepam, lorazepam, temazepam, alprazolam. |
| Anti-anxiety, other | Buspirone. |
| Mixed | Dextromethorpan/Quinidine. |
| Hormones (antiandrogens, estrogens, gonadotropin-releasing hormone analogues) | medroxyprogesterone acetate, cyproterone acetate, leuprolide. |
| Cannabinoids | medical marijuana. |
**References**
1. Plassman BL, Langa KM, Fisher GG, et al. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology. 2007;29(1-2):125-32. doi: 10.1159/000109998. PMID: 17975326.
2. Langa KM, Larson EB, Crimmins EM, et al. A Comparison of the Prevalence of Dementia in the United States in 2000 and 2012. JAMA Intern Med. 2017 Jan 01;177(1):51-8. doi: 10.1001/jamainternmed.2016.6807. PMID: 27893041.
3. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. doi: 10.1016/j.jalz.2011.03.005. PMID: 21514250.
4. Hurd MD, Martorell P, Delavande A, et al. Monetary costs of dementia in the United States. N Engl J Med. 2013 Apr 4;368(14):1326-34. doi: 10.1056/NEJMsa1204629. PMID: 23550670.
5. Zhao QF, Tan L, Wang HF, et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord. 2016 Jan 15;190:264-71. doi: 10.1016/j.jad.2015.09.069. PMID: 26540080.
6. What is Alzheimer's? Alzheimer's Association. *www.alz.org/alzheimers-dementia/what-is-alzheimers.* Accessed on November 2, 2018.
7. Alzheimer's Disease. Centers for Disease Control and Prevention. *www.cdc.gov/aging/aginginfo/alzheimers.htm.* Accessed on November 2, 2018.
8. Association AP. Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-IIIR); 1987.
9. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. PMID: 6610841.
10. Association AP. Diagnostic and Statistical Manual of Mental Disorders: DSM-5; 2013.
11. Cure S, Abrams K, Belger M, et al. Systematic literature review and meta-analysis of diagnostic test accuracy in Alzheimer's disease and other dementia using autopsy as standard of truth. J Alzheimers Dis. 2014;42(1):169-82. doi: 10.3233/JAD-131559. PMID: 24840572.
12. Frisoni GB, Boccardi M, Barkhof F, et al. Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers. Lancet Neurol. 2017 Aug;16(8):661-76. doi: 10.1016/S1474-4422(17)30159-X. PMID: 28721928.
13. Kane RLB, M.; Fink, H.A.; Brasure, M.; Davila, H.; Desai, P.; Jutkowitz, E.; McCreedy, E.; Nelson, V.A.; McCarten, J.R.; Calvert, C.; Ratner, E.; Hemmy, L.S.; Barclay, T. Interventions To Prevent Age-Related Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer's-Type Dementia. AHRQ Publication No. 17-EHC008-EF. Rockville, MD: Quality AfHRa; February 2017 2017. *www.effectivehealthcare.ahrq.gov/reports/final.cfm*
14. Reus VI, Fochtmann LJ, Eyler AE, et al. The American Psychiatric Association Practice Guideline on the Use of Antipsychotics to Treat Agitation or Psychosis in Patients With Dementia. Am J Psychiatry. 2016 May 1;173(5):543-6. doi: 10.1176/appi.ajp.2015.173501. PMID: 27133416.
15. Brasure M, Jutkowitz E, Fuchs E, et al. Nonpharmacologic Interventions for Agitation and Aggression in Dementia. Rockville (MD); 2016.
16. Qaseem A, Snow V, Cross JT, Jr., et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008 Mar 4;148(5):370-8. PMID: 18316755.
17. Kales HC, Gitlin LN, Lyketsos CG. Assessment and management of behavioral and psychological symptoms of dementia. BMJ. 2015 Mar 2;350:h369. doi: 10.1136/bmj.h369. PMID: 25731881.
18. Ruthirakuhan MT, Herrmann N, Abraham EH, et al. Pharmacological interventions for apathy in Alzheimer's disease. Cochrane Database Syst Rev. 2018 May 4;5:CD012197. doi: 10.1002/14651858.CD012197.pub2. PMID: 29727467.
19. McCleery J, Cohen DA, Sharpley AL. Pharmacotherapies for sleep disturbances in dementia. Cochrane Database Syst Rev. 2016 Nov 16;11:CD009178. doi: 10.1002/14651858.CD009178.pub3. PMID: 27851868.
20. Hackshaw A. Small studies: strengths and limitations. Eur Respir J. 2008 Nov;32(5):1141-3. doi: 10.1183/09031936.00136408. PMID: 18978131.
21. Viswanathan M, Ansari M, Berkman N, et al. Assessing the Risk of Bias of Individual Studies in Systematic Reviews of Health Care Interventions AHRQ. 2012.
22. Methods Guide for Medical Test Reviews. AHRQ Publication No. 12-EC017. Rockville, MD: Quality AfHRa; June 2012. *www.effectivehealthcare.ahrq.gov/reports/final.cfm.*
23. Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011 Oct 18;155(8):529-36. doi: 10.7326/0003-4819-155-8-201110180-00009. PMID: 22007046.
24. Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017 Sep 21;358:j4008. doi: 10.1136/bmj.j4008. PMID: 28935701.
25. Fu R, Gartlehner G, Grant M, et al. Conducting quantitative synthesis when comparing medical interventions: AHRQ and the Effective Health Care Program. J Clin Epidemiol. 2011 Nov;64(11):1187-97. doi: 10.1016/j.jclinepi.2010.08.010. PMID: 21477993.
26. Takwoingi Y. Meta-analysis of test accuracy studies in Stata: a bivariate model approach. Version 1.1.
27. Owens DK, Lohr KN, Atkins D, et al. AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions—agency for healthcare research and quality and the effective health-care program. J Clin Epidemiol. 2010 May;63(5):513-23. doi: S0895-4356(09)00093-6 [pii] 10.1016/j.jclinepi.2009.03.009. PMID: 19595577.
28. Singh S, Chang SM, Matchar DB, et al. Chapter 7: grading a body of evidence on diagnostic tests. J Gen Intern Med. 2012 Jun;27 Suppl 1:S47-55. doi: 10.1007/s11606-012-2021-9. PMID: 22648675.
29. Berkman ND, Lohr KN, Ansari M, et al. Grading the Strength of a Body of Evidence When Assessing Health Care Interventions for the Effective Health Care Program of the Agency for Healthcare Research and Quality: An Update. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville (MD); 2008.
30. Atkins D, Chang S, Gartlehner G, et al. Assessing the Applicability of Studies When Comparing Medical Interventions. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville (MD); 2008.
Francis D. Chesley, Jr.,
Acting Deputy Director.