The Nun study: clinically silent AD, neuronal hypertrophy, and linguistic skills in early life

Abstract

Background: It is common to find substantial Alzheimer disease (AD) lesions, i.e., neuritic beta-amyloid plaques and neurofibrillary tangles, in the autopsied brains of elderly subjects with normal cognition assessed shortly before death. We have termed this status asymptomatic AD (ASYMAD). We assessed the morphologic substrate of ASYMAD compared to mild cognitive impairment (MCI) in subjects from the Nun Study. In addition, possible correlations between linguistic abilities in early life and the presence of AD pathology with and without clinical manifestations in late life were considered.

Methods: Design-based stereology was used to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in the CA1 region of hippocampus (CA1). Four groups of subjects were compared: ASYMAD (n = 10), MCI (n = 5), AD (n = 10), and age-matched controls (n = 13). Linguistic ability assessed in early life was compared among all groups.

Results: A significant hypertrophy of the cell bodies (+44.9%), nuclei (+59.7%), and nucleoli (+80.2%) in the CA1 neurons was found in ASYMAD compared with MCI. Similar differences were observed with controls. Furthermore, significant higher idea density scores in early life were observed in controls and ASYMAD group compared to MCI and AD groups.

Conclusions: 1) Neuronal hypertrophy may constitute an early cellular response to Alzheimer disease (AD) pathology or reflect compensatory mechanisms that prevent cognitive impairment despite substantial AD lesions; 2) higher idea density scores in early life are associated with intact cognition in late life despite the presence of AD lesions.

Figure 1 Cell body, nuclear, and nucleolar markers for morphometric measurements (A) Large coronal section of a formalin-fixed brain of a control subject (left hemisphere). (B) Single pyramidal neuron from the CA1-hippocampus region, the specific markers for the morphometric measurements of cell body (a), nucleus (b), and nucleolus (c). The pictures of a, b, and c were realized with a digital camera connected with a light microscope using an oil-objective at 100× magnification.

Figure 2 Pyramidal neurons in 2 different clinicopathologic conditions (A) Large coronal section of a formalin-fixed brain of a control subject (left hemisphere). (B) Cell body, nuclear, and nucleolar contours of a single pyramidal neuron from the CA1-hippocampus region of an asymptomatic Alzheimer disease (ASYMAD) (a, b, c) and control (d, e, f) subject. Notice the clear enlargements of all 3 neuronal compartments in the ASYMAD subject compared to the age-matched control subject.

Figure 3 Cell bodies, nuclei, and nucleoli volumes in CA1 neurons of controls, asymptomatic Alzheimer disease (ASYMAD), mild cognitive impairment, and Alzheimer disease Box plots showing the volumes of the (A) cell bodies, (B) nuclei, and (C) nucleoli of CA1 neurons. Note the marked and significant hypertrophy of cell bodies, nuclei, and nucleoli in ASYMAD compared with other groups. *p < 0.05, **p < 0.01, ***p < 0.001. The bar across the box is the median. The lowest and highest lines at the end of the whiskers correspond to the smallest and the largest sample values.

Figure 4 Linguistic ability in early life in 2 groups of subjects with an autopsy-confirmed diagnosis 5 decades later (A) Subjects with intact cognition at death (controls and asymptomatic Alzheimer disease [ASYMAD]) compared with subjects with cognitive deficits (mild cognitive impairment [MCI] and Alzheimer disease) showed a higher idea density mean score. (B) By contrast, a significant difference between the 2 samples was not observed for the grammatic complexity mean score.