. Microdosing of scopolamine as a "cognitive stress test": rationale and test of a very low dose in an at-risk cohort of older adults. Alzheimers Dement. 2014 Mar;10(2):262-7. PubMed.

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  1. Hypersensitivity to drug-induced adverse cognitive effects and preclinical Alzheimer's disease.

    I read with interest the recent paper by Snyder and colleagues (1) on the possible use of a scopolamine challenge as a "cognitive stress test" to identify cognitively intact individuals with preclinical Alzheimer's disease (AD).

    Nearly 20 years ago, we suggested that hypersensitivity to the adverse cognitive effects of the same pharmacological challenge might identify healthy elderly Apoe4 carriers at increased risk for progressive cognitive decline and AD (2).  We subsequently demonstrated in double-blind placebo control studies that cognitively intact carriers with at least one Apoe4 allele experienced more profound dose-dependent anterograde amnestic effects, greater mental slowing, and slower recovery compared to non-carriers after acute oral administration of single doses of the antimuscarinic agent trihexyphenidyl (3,4).  A similar, albeit more subtle, pattern was also observed after acute oral lorazepam administration (5).

    Importantly, the hypersensitivity for drug-induced cognitive toxicity associated with Apoe4 could not be ascribed to pharmacokinetic factors such as differences in plasma drug levels, suggesting a pharmacodynamic basis for our results.

    However, presently it is not known if the aforementioned hypersensitivity has any prognostic significance, if it is influenced by existing AD brain pathology, and, more importantly, if it might be combined with established cerebrospinal fluid and brain AD biomarkers to enhance our ability to identify individuals with preclinical AD. Thus the scopolamine challenge study conducted by Snyder and colleagues is an additional step in addressing some of these theoretically and clinically important questions by its inclusion of a PET measure of brain amyloid burden. More specifically they will determine if an increased cortical Aβ burden will be associated with increased pharmacodynamic response to scopolamine. In this first report they focused on 26 healthy individuals having two risk factors for AD but with low Aβ based on a standardized uptake value ratio (SUVR) <1.1.  Data on the APOE genotype was not provided. Subcutaneous administration of a single 0.2 mg scopolamine dose to this population produced a reliable transient impairment in a measure of spatial working memory and new learning which peaked at three hours post-injection and normalized by five hours. The authors did not comment if SUVR influenced pharmacodynamic scopolamine response in this group and are conducting additional challenge studies in those with high Aβ to address this question. However, their pharmacological paradigm does not include a placebo condition; consequently, non-specific, well-known deleterious effects of fatigue and other factors on performance during the relatively long duration of the acute experiment which might confound the scopolamine-induced deficits cannot be quantified. Similarly, Aβ -independent mechanisms may also contribute to the increased pharmacodynamic sensitivity associated with e4. Thus, these factors will need to be addressed for valid pharmacodynamic predictors of cortical amyloid burden to emerge.

    References:

    . Microdosing of scopolamine as a "cognitive stress test": rationale and test of a very low dose in an at-risk cohort of older adults. Alzheimers Dement. 2014 Mar;10(2):262-7. PubMed.

    . Scopolamine-induced impairment as a potential predictor of Alzheimer's disease in individuals with Apolipoprotein E type 4 alleles. Neurochem Res. 1995 Dec;20(12):1519-20. PubMed.

    . Increased anticholinergic challenge-induced memory impairment associated with the APOE-epsilon4 allele in the elderly: a controlled pilot study. Neuropsychopharmacology. 2004 Feb;29(2):403-9. PubMed.

    . Increased mental slowing associated with the APOE epsilon4 allele after trihexyphenidyl oral anticholinergic challenge in healthy elderly. Am J Geriatr Psychiatry. 2008 Feb;16(2):116-24. PubMed.

    . Apolipoprotein E epsilon4 allele and lorazepam effects on memory in high-functioning older adults. Arch Gen Psychiatry. 2005 Feb;62(2):209-16. PubMed.