Olfactory 'Stress Test' May Detect Preclinical Alzheimer's
Olfactory 'Stress Test' May Detect Preclinical Alzheimer's
Table 1 summarises the characteristics of the sample by cognitive category. All participants were 65 years or older (mean 75.0, SD 6.0); mean years of education was 10.9 (SD 3.0); 25 (45%) of the subjects were males and 31 (55%) females. The initial sample comprised 29 cognitively normal (NC), 14 with cognitive impairment (CI) and 17 meeting clinical criteria for AD. Two individuals with dementia meeting clinical criteria for AD performed at chance level (5/20) on baseline testing with the UPSIT_20 and another was found to have lacunar infarcts bilaterally in the hippocampi (her atropine effect (AE) was 0). One participant with CI was noted to have changes of a right parietal lobe stroke that may have affected her cognition (her AE was also 0). These individuals were all excluded from further analyses. Three individuals declined MRI scanning, and two had contraindications to MRI scanning but all were retained in the sample, leaving 56 in all.
There were significant cognitive group-specific differences in MMSE (NC, CI > AD), global ARCS (NC > CI > AD), and scaled memory domain scores (NC > CI, AD). Mean baseline UPSIT scores (UP_20) did not differ between NC and CI, but both were significantly greater than that for the AD group (Table 1). By contrast, mean AE differed between NC and both CI and AD groups, but there were no group-specific differences in AE between CI and AD. Similar findings were present for left hippocampal volume, adjusted for ICV (LHCV), which was greater in the NC than in either CI or AD groups.
AE ranged from +5 to −6. Figure 1 depicts the distribution of AE by cognitive category. AE < 0 was present in 31% NC, 92% with CI and 86% with AD. Figure 2 shows the scatter plot of AE against scaled memory score. Figure 3 shows the scatter plot of AE and LHCV.
(Enlarge Image)
Figure 1.
Atropine effect by cognitive group. NC: Normal Control; CI: Cognitive Impairment; AD: Alzheimer's disease. Box & whiskers plots showing the median as a line and the boxes representing the inter-quartile range (25%-75%). Whiskers indicate 5–5 percentile. In terms of the atropine effect score, impaired study participants were much more like those with clinically diagnosed Alzheimer's disease than controls, however there was broad overlap. AE < 0 was present in 9/29 (31%) NC, 12/13 (92%) with CI and 12/14 (86%) with AD. The rates of AE < 0 in the normal controls and individuals with AD in this study are very similar to the rates of underlying AD at autopsy reported in the literature in comparable clinical groups.
(Enlarge Image)
Figure 2.
Atropine effect vs. scaled memory domain score. Almost without exception, low memory performance is associated with negative atropine effect (r = 0.57, P < 0.0001), but among those who perform well on memory performance there is a substantial range of atropine effect.
(Enlarge Image)
Figure 3.
Atropine effect vs. left hippocampal volume. A strong relationship exists between atropine effect and hippocampal volume (r = 0.53, P = 0.0001) with more negative scores on AE associated with more atrophic hippocampi.
The univariate associations between AE, baseline UPSIT_20, LHCV, APOE genotype and scaled cognitive domain scores are depicted in Table 2. Correlations within the entire sample and in the non-demented sub-sample showed highly significant associations between AE, scaled memory domain score and LHCV. Baseline UPSIT_20 score was significantly associated with memory, but not with either LHCV or APOE genotype. Within the dementia sample, LHCV was significantly associated with overall cognition, memory, and visuospatial function.
We conducted a series of linear regression analyses within the non-demented sample with memory domain score as the outcome. (See Table 3). In hierarchical regression analyses, age, gender and education were entered together, then baseline UPSIT_20 score and then either LHCV (Model 1) or AE (Model 2) separately. AE explained more variance (24%) in memory scores than did LHCV (15%). Next, we entered the same 4 initial variables, then AE followed by LHCV (Model 3). In this model, LHCV explained only 2% additional variance in memory, after accounting for that explained by AE. By contrast, in Model 4 in which AE was entered after LHCV, AE accounted for an additional 15% in the variance: equal to that explained by LHCV in the same model. Analytic models run without baseline UPSIT_20 score gave essentially the same results. Finally, in a linear regression model predicting memory domain score with age, gender, education, LHCV and AE entered simultaneously, AE (t = 3.3, p = 0.003) but not LHCV (t = 1.2, p = 0.24) retained significance.
One or more APOE ε4 alleles were present in 50% of individuals with dementia, 46% with CI, and 31% NC (χ =1.76, p = 0.41). Relative to no ε4, the presence of ε4 was associated with lower mean AE in the entire sample (any ε4: −2.14, no ε4: −0.44, t-test, p = 0.014), in non-demented individuals (any ε4: −1.73, no ε4: −0.07, p = 0.056) and in those with dementia (any ε4: −3.00, no ε4: −1.86, p = 0.15). The percentages of AE <0 in the NC (31%) and AD (86%) subgroups were very similar to the respective rates of AD pathology at autopsy in cognitively normal samples and clinically diagnosed AD, so we chose AE <0 as potentially indicative of underlying AD pathology for the purposes of exploratory analyses. Within the entire sample, with the AE < 0 as the outcome in a binary logistic regression adjusted for age, any APOE ε4 (relative to no ε4) was associated with significantly increased risk (Odds Ratio (OR) 3.53, 95% confidence interval 1.09–09.38). Limiting the analysis to the non-demented sample (OR 3.17, 95% confidence interval 0.84–84.94) slightly reduced the odds, with loss of statistical significance.
Finally, in analyses stratified by APOE status, correlations between AE and scaled memory score (no ε4 (n = 34) r = 0.58, p < 0.001; any ε4 (n = 22) r = 0.49, p < 0.05), and AE and LHCV (no ε4 (n = 30) r = 0.56, p = 0.001; any ε4 (n = 21) r = 0.44, p < 0.05), retained statistical significance.
Results
Table 1 summarises the characteristics of the sample by cognitive category. All participants were 65 years or older (mean 75.0, SD 6.0); mean years of education was 10.9 (SD 3.0); 25 (45%) of the subjects were males and 31 (55%) females. The initial sample comprised 29 cognitively normal (NC), 14 with cognitive impairment (CI) and 17 meeting clinical criteria for AD. Two individuals with dementia meeting clinical criteria for AD performed at chance level (5/20) on baseline testing with the UPSIT_20 and another was found to have lacunar infarcts bilaterally in the hippocampi (her atropine effect (AE) was 0). One participant with CI was noted to have changes of a right parietal lobe stroke that may have affected her cognition (her AE was also 0). These individuals were all excluded from further analyses. Three individuals declined MRI scanning, and two had contraindications to MRI scanning but all were retained in the sample, leaving 56 in all.
There were significant cognitive group-specific differences in MMSE (NC, CI > AD), global ARCS (NC > CI > AD), and scaled memory domain scores (NC > CI, AD). Mean baseline UPSIT scores (UP_20) did not differ between NC and CI, but both were significantly greater than that for the AD group (Table 1). By contrast, mean AE differed between NC and both CI and AD groups, but there were no group-specific differences in AE between CI and AD. Similar findings were present for left hippocampal volume, adjusted for ICV (LHCV), which was greater in the NC than in either CI or AD groups.
AE ranged from +5 to −6. Figure 1 depicts the distribution of AE by cognitive category. AE < 0 was present in 31% NC, 92% with CI and 86% with AD. Figure 2 shows the scatter plot of AE against scaled memory score. Figure 3 shows the scatter plot of AE and LHCV.
(Enlarge Image)
Figure 1.
Atropine effect by cognitive group. NC: Normal Control; CI: Cognitive Impairment; AD: Alzheimer's disease. Box & whiskers plots showing the median as a line and the boxes representing the inter-quartile range (25%-75%). Whiskers indicate 5–5 percentile. In terms of the atropine effect score, impaired study participants were much more like those with clinically diagnosed Alzheimer's disease than controls, however there was broad overlap. AE < 0 was present in 9/29 (31%) NC, 12/13 (92%) with CI and 12/14 (86%) with AD. The rates of AE < 0 in the normal controls and individuals with AD in this study are very similar to the rates of underlying AD at autopsy reported in the literature in comparable clinical groups.
(Enlarge Image)
Figure 2.
Atropine effect vs. scaled memory domain score. Almost without exception, low memory performance is associated with negative atropine effect (r = 0.57, P < 0.0001), but among those who perform well on memory performance there is a substantial range of atropine effect.
(Enlarge Image)
Figure 3.
Atropine effect vs. left hippocampal volume. A strong relationship exists between atropine effect and hippocampal volume (r = 0.53, P = 0.0001) with more negative scores on AE associated with more atrophic hippocampi.
The univariate associations between AE, baseline UPSIT_20, LHCV, APOE genotype and scaled cognitive domain scores are depicted in Table 2. Correlations within the entire sample and in the non-demented sub-sample showed highly significant associations between AE, scaled memory domain score and LHCV. Baseline UPSIT_20 score was significantly associated with memory, but not with either LHCV or APOE genotype. Within the dementia sample, LHCV was significantly associated with overall cognition, memory, and visuospatial function.
We conducted a series of linear regression analyses within the non-demented sample with memory domain score as the outcome. (See Table 3). In hierarchical regression analyses, age, gender and education were entered together, then baseline UPSIT_20 score and then either LHCV (Model 1) or AE (Model 2) separately. AE explained more variance (24%) in memory scores than did LHCV (15%). Next, we entered the same 4 initial variables, then AE followed by LHCV (Model 3). In this model, LHCV explained only 2% additional variance in memory, after accounting for that explained by AE. By contrast, in Model 4 in which AE was entered after LHCV, AE accounted for an additional 15% in the variance: equal to that explained by LHCV in the same model. Analytic models run without baseline UPSIT_20 score gave essentially the same results. Finally, in a linear regression model predicting memory domain score with age, gender, education, LHCV and AE entered simultaneously, AE (t = 3.3, p = 0.003) but not LHCV (t = 1.2, p = 0.24) retained significance.
Apolipoprotein E Associations
One or more APOE ε4 alleles were present in 50% of individuals with dementia, 46% with CI, and 31% NC (χ =1.76, p = 0.41). Relative to no ε4, the presence of ε4 was associated with lower mean AE in the entire sample (any ε4: −2.14, no ε4: −0.44, t-test, p = 0.014), in non-demented individuals (any ε4: −1.73, no ε4: −0.07, p = 0.056) and in those with dementia (any ε4: −3.00, no ε4: −1.86, p = 0.15). The percentages of AE <0 in the NC (31%) and AD (86%) subgroups were very similar to the respective rates of AD pathology at autopsy in cognitively normal samples and clinically diagnosed AD, so we chose AE <0 as potentially indicative of underlying AD pathology for the purposes of exploratory analyses. Within the entire sample, with the AE < 0 as the outcome in a binary logistic regression adjusted for age, any APOE ε4 (relative to no ε4) was associated with significantly increased risk (Odds Ratio (OR) 3.53, 95% confidence interval 1.09–09.38). Limiting the analysis to the non-demented sample (OR 3.17, 95% confidence interval 0.84–84.94) slightly reduced the odds, with loss of statistical significance.
Finally, in analyses stratified by APOE status, correlations between AE and scaled memory score (no ε4 (n = 34) r = 0.58, p < 0.001; any ε4 (n = 22) r = 0.49, p < 0.05), and AE and LHCV (no ε4 (n = 30) r = 0.56, p = 0.001; any ε4 (n = 21) r = 0.44, p < 0.05), retained statistical significance.