Medial temporal lobe volume is associated with neuronal loss but not with hippocampal microinfarcts despite their high frequency in aging brains

Highlights

• Hippocampal microinfarcts are very common in old age (>50%).

• Mesiotemporal atrophy is closely correlated with neuronal loss.

• Mesiotemporal atrophy is not related to the volume of hippocampal microinfarcts.

Abstract

Medial temporal lobe (MTL) atrophy is an important marker for the clinical diagnosis of Alzheimer's disease at its prodromal stages. Several brain lesions have been associated with MTL atrophy including hippocampal sclerosis, neurodegenerative neuronal loss, and vascular pathology. To better explore the relationship between MTL volume on MRI and age-related degenerative and microvascular hippocampal pathology, we compared MTL volume on postmortem whole brain MRI and stereological estimates of the total number of neurons, cortical microinfarcts (CMIs), and neurofibrillary tangles (NFTs) in a consecutive autopsy series of 21 older individuals (11 females and 10 males, mean age 83.3 ± 5.8; range: 74–93 years, 7 demented and 14 nondemented). Our results revealed a very high percentage of cases with hippocampal CMIs (52%), particularly in the CA1 field. MTL volume was closely related to neuronal loss in both the CA1 area of the hippocampus (p = 0.0109) and the entorhinal cortex (p = 0.0272). MTL volume was not related to total CMI volume or to the total number of NFTs in our sample. In conclusion, hippocampal CMIs are very common in old age. MTL volume is determined essentially by the number of neurons in the hippocampus and does not appear to be related to the presence of NFTs or CMIs in this region.

Introduction

The medial temporal lobe (MTL) contains structures involved in memory processes and is affected early in various dementing disorders (Giannakopoulos et al., 2009; Silverberg et al., 2011). Visual assessment rating scales for MTL volume have long been used in clinical practice to support the diagnosis of Alzheimer's disease (AD) (Westman et al., 2011). Moreover, MTL measurement is a good alternative to hippocampal volumetry for the identification of patients at high risk for AD among those with minor cognitive impairment (for review, see Ten Kate et al., 2017). However, numerous other brain pathologies such as hippocampal sclerosis (HS) (Dawe et al., 2011), frontotemporal dementia (FTD) (Bocchetta et al., 2018; Whitwell and Josephs, 2012), and several psychiatric disorders such as schizophrenia (Wright et al., 2000) have also been associated with MTL atrophy.

Among vascular brain pathologies, HS is a well-known cause of MTL atrophy (Dawe et al., 2011). Clinically it may mimic AD (Leverenz et al., 2002; Zarow et al., 2008) and is oftentimes misdiagnosed even on antemortem brain imaging. In contrast to HS, little is known about the effect of multiple cortical microinfarcts (CMIs) on hippocampal volume. CMIs are small cortical ischemic lesions measuring several hundred μm and seen only on histological examination (Gold et al., 2007; Smith et al., 2012). They are present as sharply demarcated intracortical lesions. In acute or subacute lesions, cellular death and small necrotic foci are seen, replaced later, in chronic lesions, by a gliotic scar. CMIs tend to occur in junctional vascular zones. They are particularly common in older individuals and highly correlated with cognitive function in this age group (Brundel et al., 2012; Corrada et al., 2016; Gold et al., 2007, 2005; Kalaria et al., 2004; Kapasi et al., 2018; Kövari et al., 2004, Kövari et al., 2007). During routine neuropathological diagnosis, only a small part of the hippocampus is examined and many CMIs may be missed. Stereological approaches can provide a more exact assessment of the number of CMIs in this particular brain region.

Radiopathological correlations using antemortem MRI can be difficult to interpret as the elapsed time between imaging and the neuropathological examination may be quite variable and often too long for reliable comparisons. This issue can be addressed by performing postmortem MRI as part of the autopsy procedure which makes it possible to explore the relationship between neuropathological findings and MTL volume measured within the same timeframe. We report here a radiopathological study applying this methodology to identify the main underlying lesions associated with MTL atrophy in an elderly population.