In our prospective, cross-sectional study of SAA, which has been proposed for delirium screening [7
], we detected substantial SAA levels in frail, often demented, elderly. However, SAA levels revealed to be independent of delirium and dementia diagnoses and did not correlate with cognitive impairment. Nor did we find a correlation with any rEEG or qEEG parameter known to be affected by the central anticholinergic action of scopolamine [25
], and by delirium [26
]. At least in oldest-old geriatric inpatients, SAA levels do not seem to reflect the cerebral situation as measured by clinical means and by EEG.
High SAA levels indicated a significant anticholinergic burden detectable in the serum of all subgroups of frail elderly with acute medical conditions, but were not related to delirium and dementia diagnosis. SAA levels reported in the literature were measured with comparable methodology but revealed rather divergent levels [7
], presumably due to the different populations studied. Our SAA levels of frail elderly were in line with those of other investigations in comparable settings [8
], though some groups found much smaller SAA in quite similar patients [9
] especially in patients without delirium.
In our study, SAA levels did not differ in DD patients and the D or CU subgroups which argues against the hypothesis of a direct relation between delirium and SAA. The two comparable studies reporting a significant SAA difference in delirium [10
] exhibited several methodological drawbacks. Delirium diagnosis in both studies was based on screening instruments only, without psychiatric evaluation; centrally acting anticholinergic drugs were significantly more common with high SAA and delirium [10
]; outlier biases occurred [10
] and infection was the strongest delirium predictor. As in our study, SAA did not correlate with definite anticholinergic drugs overall.[12
] Also, delirium itself did not correlate with an overall anticholinergic burden but with specific centrally active drugs [42
]. Endogenous contributions to SAA, related to fever and infection rather than delirium, and probably mediated through stress mechanisms were recently detected[13
]. In animals, stress-induced hyperthermia was found to be modulated by a peripheral cholinergic mechanism [44
]. It is therefore hypothesized that stress- and fever related endogenous anticholinergic activity operates in the periphery [22
In conclusion, SAA must be considered as a conglomerate of anticholinergic properties of endogenous and exogenous origin, which act on peripheral targets and only possibly on the CNS. Our results suggest, that SAA reflects predominantly non-central-acting and medication-independent components in frail oldest old with acute disease.
Typical EEG changes represent the gold standard of delirium diagnosis[26
] and our EEG results are in line with these findings in delirium [28
] and with dementia studies [26
]. REEG and qEEG parameters correlated closely with delirium severity and cognitive impairment underlining their relation to cholinergic activation.
EEG again confirms our expert panel based clinical subgroup classification, but neither rEEG nor qEEG parameters correlated with SAA levels. EEG patterns of centrally acting anticholinergics such as scopolamine closely resemble delirium changes in normal [25
] and demented subjects [46
] while peripheral anticholinergics do not exhibit EEG changes [27
]. Thus, the lack of any correlation of SAA with EEG parameters again gives strong evidence that SAA in our sample of frail elderly does not reflect the cerebral cholinergic situation. We confirmed this recently in a younger sample of various ICU patients[47
], where SAA levels were found to be lower, but also did not correlate to delirium and EEG measures.
In our frail elderly population no association was observed between the anticholinergic burden and cognitive deficits, not even in dementia. This finding is contrary to previous studies describing an association of SAA with lower MMSE [17
], restricted in some to demented patients [9
], or to specific memory tests [16
]. Others reported no connection in non-demented elderly [14
]. Reasons for these discrepancies include: Individual variations due to white matter load [21
] and ApoE status [48
], which have been shown to influence cognitive performance and cognitive challenge recovery in non-demented elderly. Dose-dependent influences of centrally acting anticholinergics are also probable [14
] and may have been overlooked. In Chew's sample, e.g., most demented subjects had received lorazepam [9
], which was recently reconfirmed by fMRT to impair memory [49
] and facilitates delirium transition [50
]. On the other hand, as MMSE is a rather crude measure of memory functions, slight differences might have been detectable with more sophisticated tests on working memory and delayed recall in our sample, as anticholinergic medication in general has been proven to influence memory function in a subtler way.[1
However, we did find a moderate correlation of SAA with functional outcome, indicating a negative influence of the anticholinergic burden on functional capacity in D and in acutely ill CU, supporting a former study [18
]. In DD correlation was lacking, indicating functional deficits caused by additional mechanisms. Functional impairment may be caused by peripheral side effects like accommodation difficulties, brady- or tachycardia and gate disturbance.[20
] On the other hand, peripheral cholinergic pathways have also been described to influence memory performance in mice [51
], but this awaits confirmation in humans.
Our study has several limitations. A larger sample size might have clarified the correlation with the patients' daily functions. Additionally, more extensive neuropsychological assessment could evaluate specific but subtle cognitive changes, e.g. memory disturbance. The additional assessment of CSF-AA with SAA and EEG parameters would have strengthened conclusions regarding their association. The correlation of CSF-AA and SAA with individual substances and in different patient samples remains to be assessed. Further studies on the central pharmacodynamics of individual substances and on blood-brain-barrier permeability in the elderly are needed. Finally, our sample did not include delirium patients without a prior cognitive decline. These patients must be studied within a younger patient group with lower dementia prevalence.