While the population-attributable risk estimates are very helpful in considering the burden of diseases that can cause dementia in the ACT cohort, they do not reflect the complex mixtures of diseases that may exist in individuals. To demonstrate this complexity visually, we devised a “summary neuropathology score” that is the sum of: (i) Braak stage for NFTs expressed as a number (0 to 6) divided by 2 to give values of 0, 0.5, 1, 1.5, 2, 2.5, and 3; (ii) number of CMIs with > 3 expressed as 3 to give a values of 0, 1, 2, or 3; and (iii) LBD coded as 0 (none), 1 (brainstem), 2 (limbic), or 3 (isocortical). Thus the minimum score is 0 and the maximum is 9. The same numerical score could represent different disease contributors to cognitive impairment or dementia. For example, a cumulative neuropathology score of 1.5 could translate into a Braak stage for NFTs of III if only AD was present, or a Braak stage for NFTs of II and 1 CMI. Although the RR for causing dementia is similar for each disease, they are not identical and thus the score is not strictly weighted. Nevertheless, the RRs are similar and so scaling each disease from scores of 0 to 3 and expressing the sum provides a simple visual representation of the co-morbid burden of disease in a given individual.
As a first analysis we divided the ACT autopsy cohort of individuals with last clinical evaluation within two years of death into three functionally-defined subsets: Dementia, Not Dementia (ND) with low cognitive function, and ND with high cognitive function. Dementia or ND was diagnosed using DSM-IV criteria. The ND group was divided into low and high cognitive function by CASI score [7
]. CASI is a 100-point scale, and among the entire ACT cohort, scores < 90 are in the lowest quintile. The ND low cognitive function group had last CASI < 90. The ND high cognitive function group had CASI > 90.
plots the cumulative relative frequency (CRF) of the overall summary neuropathology score for these three groups. As expected, the overall burden of diseases progresses from lowest in the ND & CASI > 90 group to highest in the Dementia group. One summary estimate of disease burden is 50% of total CRF (CRF50). The CRF50 for summary neuropathology score progressively increased from approximately 1.25 in the highest functioning group (ND & CASI > 90), to 2.0 for the intermediate functioning group (ND & CASI < 90), to 3.5 for the lowest functioning group (Dementia). Non-parametric ANOVA (Kruskal-Wallis test) of the summary neuropathology score among these three functionally-defined groups had P < 0.0001 and Dunn’s corrected repeat paired comparison had P < 0.01 for each of the three pairs. These cross sectional observations from groups defined by cognitive performance within two years of death indicate that increasing overall burden of diseases that can contribute to the dementia syndrome is significantly associated with decreasing cognitive function.
Figure 2 Cumulative relative frequency (CRF) of the summary neuropathology score calculated from the sum of: (i) Braak stage for NFTs expressed as a number (0 to 6) divided by 2 to give values of 0, 0.5, 1, 1.5, 2, 2.5, and 3; (ii) number of CMIs with > (more ...)
It is important to note that everyone in the highest functioning group (ND & CASI > 90) had at least some evidence of one of these diseases at autopsy, suggesting widely prevalent clinically silent disease in this group. Moreover, the burden of disease even among these high functioning individuals varied continuously from very low to high with approximately 15% having summary neuropathology scores that exceeded the CRF50 for individuals in the Dementia group. The same relationships held with the ND & CASI < 90 group but shifted to the right with approximately 25% of this group having cumulative disease burden that exceeded the CRF50 for individuals in the Dementia group.
In summary, the three diseases that are significantly associated with a clinical diagnosis of dementia in ACT participants— AD, μVBI, and LBD—are highly prevalent among individuals with high cognitive function within two years of death. Furthermore, about 15% of this group carries levels of disease that might reasonably be expected to produce dementia. While these observations are not new [3
], our summary neuropathology score provides a useful tool to express these relationships among co-morbid AD, μVBI, and LBD.