The Clinical Dementia Rating (CDR®) was developed by the multidisciplinary Dementia Study Group (DSG) at Washington University School of Medicine that, beginning in 1972, was organized and led by Leonard Berg, MD, Clinical Professor of Neurology.  The DSG eventually resolved to initiate a longitudinal study of “senile dementia of the Alzheimer type” in comparison with healthy aging and sought grant support from the National Institutes of Health.  Two cognitive psychologists, Jack Botwinick, PhD, and Martha Storandt, PhD, were instrumental in assisting Berg in submitting a successful grant application.  However, they charged Berg and the other DSG clinicians to develop a clinical staging instrument to classify research participants as either cognitively normal or impaired and, if impaired, to stage the severity of the cognitive impairment.  This clinical staging would be derived without reference to the participants’ cognitive test performances, which were to be the primary outcome measures of the proposed study, to avoid the confound inherent when test results are used both for classification and as outcome measures.  Berg and his clinical colleagues discovered a clinical staging system that yielded the following stages:  Normal (“no evidence of mental abnormality”); Mild impairment (“definitive impairment of memory and of calculating ability”); Moderate impairment (“as for mild impairment, but also disorientation for time and/or place”); and Severe impairment (“as for moderate impairment, but also difficulty with self-care”).1  Berg and colleagues incorporated detailed modifications to this system that included ratings of the severity of impairment in six separate categories, or domains, of cognitive and functional performance, providing descriptors or “anchor points” for each level of severity in each of the six domains, and devising an algorithm or “scoring rules” to use the severity levels in the six domains to yield a global Clinical Dementia Rating, where a rating of  0 indicated no cognitive impairment and a rating of 1, 2, or 3 indicated mild, moderate, or severe dementia.  Descriptions of the development and implementation of the global CDR were published.2,3

With experience, the global CDR was expanded to include an additional CDR 0.5 category denoting “questionable dementia”.  This category subsequently was determined to designate “very mild dementia” rather than “questionable dementia”.4 In 1993, additional refinements permitted resolution of ambiguities, sharpened distinctions between severity levels within each domain, and provided improved clinical scoring rules, yielding the version of the global CDR that is in use today.5

A more quantitative representation of the CDR is provided by the sum of the severity ratings for each of the six cognitive and functional domains, or “boxes”, that are used to derive the global CDR.  This more quantitative representation has a range of severity from 0 (6 “boxes” x rating of 0 in each) to 18 (6 “boxes” with rating of 3 in each) and was introduced in 1988 as the CDR Sum of Boxes.6 The Sum of Boxes (later shortened to SumBoxes, or CDR-SBTM) provides a more quantitative measure of dementia severity than the global CDR.  The CDR-SB frequently is used to assess Alzheimer disease progression in clinical research7-9 and as a primary outcome measure in Alzheimer disease clinical trials.10 Indeed, the CDR-SB was the primary outcome measure for Biogen’s two phase 3 trials of aducanumab.11 A search of ClinicalTrials.gov in 2021 found that the most widely used cognitive outcome measures in 208 registered phase 3 trials in Alzheimer disease were the Alzheimer Disease Assessment Scale-Cognitive Subscale (74 trials), the Mini-Mental State Examination (58 trials), and the CDR-SB (46 trials).9  Of these three measures, only the CDR-SB assesses both cognitive and functional performance.

References

  1. Roberts MA, Caird FI. Computerised tomography and intellectual impairment in the elderly. Journal of neurology, neurosurgery, and psychiatry. 1976;39(10):986-989.
  2. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry. 1982;140:566-572.
  3. Berg L, Hughes CP, Danziger WL, Martin RL, Knesevich J. Mild senile dementia of Alzheimer type (SDAT):  Research diagnostic criteria, recruitment, and description of a study population. J Neurol Neurosurg Psychiatry. 1982;45:962-968.
  4. Morris JC, McKeel DW, Jr., Storandt M, et al. Very mild Alzheimer’s disease: Informant-based clinical, psychometric, and pathological distinction from normal aging. Neurology. 1991;41:469-478.
  5. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43(11):2412-2414.
  6. Berg L, Miller JP, Storandt M, et al. Mild senile dementia of the Alzheimer type: 2. Longitudinal assessment. Ann Neurol. 1988;23(5):477-484.
  7. Williams MM, Storandt M, Roe CM, Morris JC. Progression of Alzheimer’s disease as measured by Clinical Dementing Rating Sum of Boxes scores. Alzheimer’s & Dementia. 2012;9:S39-44.
  8. Samtani MN, Raghavan N, Novak G, Nandy P, Narayan VA. Disease progression model for Clinical Dementia Rating-Sum of Boxes in mild cognitive impairment and Alzheimer’s subjects from the Alzheimer’s Disease Neuroimaging Initiative. Neuropsychiatric disease and treatment. 2014;10:929-952.
  9. Jutten RJ, Sikkes SAM, Van der Flier WM, Scheltens P, Visser PJ, Tijms BM. Finding Treatment Effects in Alzheimer Trials in the Face of Disease Progression Heterogeneity. Neurology. 2021;96(22):e2673-e2684.
  10. Cedarbaum JM, Jaros M, Hernandez C, et al. Rationale for use of the Clinical Dementia Rating Sum of Boxes as a primary outcome measure for Alzheimer’s disease clinical trials. Alzheimers & Dementia. 2013;9(1):S45-S55.
  11. Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. J Prev Alzheimers Dis. 2022;9(2):197-210.