A novel cognitive assessment paradigm to detect Pre-mild cognitive impairment (PreMCI) and the relationship to biological markers of Alzheimer's disease

Abstract

Objective

A number of older adults obtain normal scores on formal cognitive tests, but present clinical concerns that raise suspicion of cognitive decline. Despite not meeting full criteria for Mild Cognitive Impairment (MCI), these PreMCI states confer risk for progression to Alzheimer's disease (AD). This investigation addressed a pressing need to identify cognitive measures that are sensitive to PreMCI and are associated with brain biomarkers of neurodegeneration.

Method

Participants included 49 older adults with a clinical history suggestive of cognitive decline but normal scores on an array of neuropsychological measures, thus not meeting formal criteria for MCI. The performance of these PreMCI participants were compared to 117 cognitively normal (CN) elders on the LASSI-L, a cognitive stress test that uniquely assesses the failure to recover from proactive semantic interference effects (frPSI). Finally, a subset of these individuals had volumetric analyses based on MRI scans.

Results

PreMCI participants evidenced greater LASSI- L deficits, particularly with regards to frPSI and delayed recall, relative to the CN group. No differences on MRI measures were observed. Controlling for false discovery rate (FDR), frPSI was uniquely related to increased dilatation of the inferior lateral ventricle and decreased MRI volumes in the hippocampus, precuneus, superior parietal region, and other AD prone areas. In contrast, other LASSI-L indices and standard memory tests were not related to volumetric findings.

Conclusions

Despite equivalent performance on traditional memory measures, the frPSI distinguished between PreMCI and CN elders and was associated with reductions in brain volume in numerous AD-relevant brain regions.

Introduction

In 2011, the National Institutes on Aging and Alzheimer's Association (NIA-AA) established broad research criteria for the diagnosis of preclinical Alzheimer's disease (AD). The focus of these guidelines was to address the to define AD in terms of its underlying pathophysiological disease process rather than NIA-AA guidelines for clinical stages of the disease relative to individuals with mild cognitive impairment (MCI) who had MRI or amyloid PET evidence of AD pathology (Albert et 2011) or dementia related to Alzheimer's Disease (McKhann et al., 2011).

From a cognitive standpoint, accurately identifying individuals on the Alzheimer's disease (AD) continuum during the preclinical stages is challenging given that there are older adults who may have suspected cognitive deficits, score within normal limits on neuropsychological evaluation and do not meet formal criteria for mild cognitive impairment (MCI). These individuals, classified as PreMCI, experienced a much greater likelihood of experiencing a decline to formal MCI or dementia longitudinally than cognitively normal older adults (Loewenstein et al., 2012). In fact, the neuropsychological test performance of persons with PreMCI has also been associated with biomarkers of AD pathology (Duara et al., 2011, Loewenstein et al., 2016, Loewenstein et al., 2017a).

The ability to identify individuals with PreMCI is important since many persons evaluated may not have access to advanced neuroimaging such as amyloid PET scans and that emerging therapies, both now and in the future, are likely to be more efficacious before multisystem brain deterioration has occurred.

Recent findings have suggested that cognitive “stress tests” may be sensitive to the earliest changes in AD (Loewenstein et al., 2016). These measures are analogous to an exercise EKG that may reveal cardiac deficits that simply cannot be identified in a resting state. One such test, the LASSI-L, requires learning of 15 words belonging to three semantic categories and taps vulnerability to semantic proactive interference by presenting a competing semantically similar set of targets. A unique feature of the LASSI-L is a second presentation of the second target list that taps failure to recover from proactive semantic interference (frPSI). The LASSI-L frPSI measure has been found to be: highly related to total and regional amyloid load in neuropsychologically normal community-dwelling elders (Loewenstein et al., 2016); has differentiated between aMCI patients with suspected AD from cognitively unimpaired elderly controls (CN) (Curiel et al., 2013, Crocco et al., 2014, Matías-Guiu et al., 2016); and has been associated with volumetric loss in AD prone areas among elders with amnestic MCI (Loewenstein et al., 2017b).

The current investigation is unique in that it represents a first attempt to determine whether failure to recover from proactive semantic interference (frPSI) differentiates between older adults with PreMCI and those who are cognitively normal (CN). A further goal was to determine the extent to which frPSI was associated with volumetric structural MRI changes in AD related brain regions (Dickerson et al., 2011, Holland et al., 2009, Loewenstein et al., 2017b) among our participants.