Research Article: Metabolic correlates of reserve and resilience in MCI due to Alzheimer’s Disease (AD)

Date Published: April 3, 2018

Publisher: BioMed Central

Author(s): Matteo Bauckneht, Andrea Chincarini, Roberta Piva, Dario Arnaldi, Nicola Girtler, Federico Massa, Matteo Pardini, Matteo Grazzini, Hulya Efeturk, Marco Pagani, Gianmario Sambuceti, Flavio Nobili, Silvia Morbelli.

http://doi.org/10.1186/s13195-018-0366-y

Abstract

We explored the presence of both reserve and resilience in late-converter mild cognitive impairment due to Alzheimer’s disease (MCI-AD) and in patients with slowly progressing amyloid-positive MCI by assessing the topography and extent of neurodegeneration with respect to both “aggressive” and typically progressing phenotypes and in the whole group of patients with MCI, grounding the stratification on education level.

We analyzed 94 patients with MCI-AD followed until conversion to dementia and 39 patients with MCI who had brain amyloidosis (AMY+ MCI), all with available baseline 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) results. Using a data-driven approach based on conversion time, patients with MCI-AD were divided into typical AD and late-converter subgroups. Similarly, on the basis of annual rate of Mini Mental State Examination score reduction, AMY+ MCI group was divided, obtaining smoldering (first tertile) and aggressive (third tertile) subgroups. Finally, we divided the whole group (MCI-AD and AMY+ MCI) according to years of schooling, obtaining four subgroups: poorly educated (Low-EDUC; first quartile), patients with average education (Average-EDUC; second quartile), highly educated (High-EDUC; third quartile), and exceptionally educated (Except-EDUC; fourth quartile). FDG-PET of typical AD, late converters, and aggressive and smoldering AMY+ MCI subgroups, as well as education level-based subgroups, were compared with healthy volunteer control subjects (CTR) and within each group using a two-samples t test design (SPM8; p < 0.05 family-wise error-corrected). Late converters were characterized by relatively preserved metabolism in the right middle temporal gyrus (Brodmann area [BA] 21) and in the left orbitofrontal cortex (BA 47) with respect to typical AD. When compared with CTR, the High-EDUC subgroup demonstrated a more extended bilateral hypometabolism in the posterior parietal cortex, posterior cingulate cortex, and precuneus than the Low- and Average-EDUC subgroups expressing the same level of cognitive impairment. The Except-EDUC subgroup showed a cluster of significant hypometabolism including only the left posterior parietal cortex (larger than the Low- and Average-EDUC subgroups but not further extended with respect to the High-EDUC subgroup). Middle and inferior temporal gyri may represent sites of resilience rather than a hallmark of a more aggressive pattern (when hypometabolic). These findings thus support the existence of a relatively homogeneous AD progression pattern of hypometabolism despite AD heterogeneity and interference of cognitive reserve. In fact, cortical regions whose “metabolic resistance” was associated with slower clinical progression had different localization with respect to the regions affected by education-related reserve. The online version of this article (10.1186/s13195-018-0366-y) contains supplementary material, which is available to authorized users.

Partial Text

18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and structural magnetic resonance imaging (MRI) have been demonstrated to reflect cognitive function and are considered progression biomarkers in patients with Alzheimer’s disease (AD) [1]. Moreover, given their capability to demonstrate neurodegeneration in vivo, both FDG-PET and MRI have significantly contributed to the understanding of cognitive reserve-related adaptive mechanisms [2–4]. In fact, given a particular level of imaging-assessed brain damage, cognitive reserve could hypothetically be defined as the difference between an individual’s expected and actual cognitive performance [5]. However, the concept of cognitive reserve and the capability of FDG-PET and MRI to capture reserve mechanisms are somehow in contrast to the emerging role and value of these techniques as predictors of clinical disease milestones, such as time to conversion from the mild cognitive impairment (MCI) to the dementia stage. Moreover, whereas a large body of literature has been devoted to assessment of the value of FDG-PET in the prediction of further cognitive decline in MCI for diagnostic purposes, only the identification and localization of regions whose metabolism is able to predict the speed of progression in patients with mild cognitive impairment due to Alzheimer’s disease (MCI-AD) may allow researchers to further address the existence of a specific interference due to cognitive reserve [6–9]. We recently demonstrated the role of FDG-PET as a significant progression biomarker in a naturalistic group of patients with MCI-AD by demonstrating that baseline middle and inferior temporal metabolism is able to capture the speed of conversion to AD dementia regardless of confounding factors such as age and education [10]. However, in our previous analysis, we did not further explore whether metabolic levels in these regions represent a marker of more aggressive disease (i.e., more marked hypometabolism accelerating conversion) or a potential site of resilience (i.e., relatively preserved metabolic levels corresponding to resistance to neurodegeneration delaying conversion in MCI-AD). In fact, whereas in patients with AD cognitive reserve is supposed to protect against the cognitive consequences of AD pathology and not against the accumulation of the pathology itself, resilience may refer to both reserve and maintenance mechanisms (i.e., resistance to brain neurodegeneration despite the presence of AD pathology) [11–13]. Although several lines of evidence support the idea that despite a greater amount of neurodegeneration, the clinical phenotype of AD in highly educated individuals may be similar to that found in patients with lower education and less pathology [14], the existence of an influence of protective factors and reserve proxies on the aggregation of AD pathology and consequent neurodegeneration is an ongoing research issue (see [15, 16] for detailed reviews). Accordingly, the existence of maintenance mechanisms in late-converter patients with MCI-AD would represent a further source of complexity in the construct of brain reserve and might explain the lack of influence of mere statistical adjustments (such as covarying for the years of education) on the value of baseline brain metabolism as a predictor of disease progression.

The present findings support the value of baseline brain metabolism as a progression biomarker in MCI-AD despite the effect of reserve-related mechanisms. In fact, on one hand, highly educated patients demonstrated a level of cognitive impairment similar to that of poorly educated patients despite a more extended hypometabolism in posterior AD-typical regions. On the other hand, late converter patients with MCI-AD and patients with smoldering AMY+ MCI demonstrated a less extended and severe hypometabolism compared with patients with typically progressing MCI-AD. These findings were actually not in contrast to one another, because we highlighted that not the posterior parietal (cognitive reserve-related) regions but specifically the right temporal cortex and in particular the middle temporal gyrus were relatively spared in both the late-converter MCI-AD and smoldering AMY+ MCI subgroups. Ewers and colleagues previously aimed to examine the effect of education on brain metabolism in subjects with preclinical AD, and in keeping with our results, they highlighted a significant interaction between education and CSF Aβ42 status in posterior cingulate cortex and angular gyrus ROIs but not in the inferior and middle temporal gyri [14]. It was also recently demonstrated that the annual changes in tau tracer binding in middle and inferior temporal gyri are significantly related to episodic memory impairments in AD [33, 34]. More interestingly, in keeping with our results, a recent combined tau-PET and FDG-PET study demonstrated that decreased FDG uptake (but not tau tracer increased uptake) in the middle and inferior temporal gyri significantly predicted decreased global functioning as assessed by MMSE score [35].

The present study suggests that the effect of education on brain metabolism may act through both reserve and resilience mechanisms in different brain regions possibly affecting the speed of progression from MCI to AD dementia stage. In fact, not the posterior parietal (cognitive reserve-related) regions but specifically the middle and inferior temporal gyri seem to be relatively spared in patients with slowly progressing MCI-AD. These findings thus support the existence of a relatively homogeneous AD progression-related pattern of hypometabolism despite AD heterogeneity and interference of cognitive reserve. Further larger studies are needed to assess whether these regions represent a more specific and topographically restricted target to test the effect of lifestyle enrichment and lifestyle-related risk factors in patients with MCI-AD.

 

Source:

http://doi.org/10.1186/s13195-018-0366-y

 

Leave a Reply

Your email address will not be published.