Variables associated with hippocampal atrophy rate in normal aging and mild cognitive impairment

Abstract

The goal of this study was to identify factors contributing to hippocampal atrophy rate (HAR) in clinically-normal older adults (NC) and participants with mild cognitive impairment (MCI). Longitudinal HAR was measured on T1-weighted MRI, and the contribution of age, gender, ApoE ε4 status, intracranial volume, white matter lesions, and β-amyloid (Aβ) levels to HAR was determined using linear regression. Age-related effects of HAR were compared in Aβ positive (Aβ+) and Aβ negative (Aβ−) participants. Age and Aβ levels had independent effects on HAR in NC, while gender, ApoE ε4 status, and Aβ levels were associated with HAR in MCI. In multivariable models, Aβ levels were associated with HAR in NC; ApoE ε4 and Aβ levels were associated with HAR in MCI. In MCI, age was a stronger predictor of HAR in Aβ− versus Aβ+ participants. HAR was higher in Aβ+ participants, but the majority of HAR was due to factors other than Aβ status. Age-related effects on HAR did not differ between NC versus MCI participants with the same Aβ status. Therefore we conclude that even when accounting for other covariates, Aβ status, and not age, is a significant predictor of HAR; and that the majority of HAR is not accounted for by Aβ status in either NC or MCI.

Cross-Sectional and Longitudinal Hippocampal Atrophy, Not Cortical Thinning, Occurs in Amyloid-Negative, p-Tau-Positive, Older Adults With Non-Amyloid Pathology and Mild Cognitive Impairment

“…Most studies of the MCI population are performed in a mixed MCI population irrespective of amyloid status or only in amyloid-positive MCI participants. Our findings are very much in accordance with previous studies of amyloid-positive MCI participants, showing higher atrophy compared with controls (Huijbers et al, 2015 ; Nosheny et al, 2015 ; Jang et al, 2019 ). Cortical thinning has been most commonly reported in the medial temporal regions, parieto-occipital regions, and the frontal regions, also known as AD-vulnerable regions.…”

Cross-Sectional and Longitudinal Hippocampal Atrophy, Not Cortical Thinning, Occurs in Amyloid-Negative, p-Tau-Positive, Older Adults With Non-Amyloid Pathology and Mild Cognitive Impairment

“…Most studies of the MCI population are performed in a mixed MCI population irrespective of amyloid status or only in amyloid-positive MCI participants. Our findings are very much in accordance with previous studies of amyloid-positive MCI participants, showing higher atrophy compared with controls (Huijbers et al, 2015 ; Nosheny et al, 2015 ; Jang et al, 2019 ). Cortical thinning has been most commonly reported in the medial temporal regions, parieto-occipital regions, and the frontal regions, also known as AD-vulnerable regions.…”

Hippocampal Volume Loss, Brain Amyloid Accumulation, and APOE Status in Cognitively Intact Elderly Subjects

“…The association between amyloid positivity and HVL in our cohort was at the level of a trend or was even nonsignificant depending on the regression models used. These observations are consistent with previous contributions indicating that amyloid burden may affect hippocampal integrity only in some vulnerable individuals, thereby accounting for a small percentage of HVL [42][43][44]. Our data parallel those in previous reports pointing to the relative independence between amyloid pathology and hippocampal structural changes in preclinical and prodromal AD cases.…”

“…HVL is known to be highly variable in the course of normal brain aging [41]. Consistent with recent contributions [42][43][44][45], the mean HVL in this series (4.5 years after inclusion) varied from 1 to 2.5%. The proportion of HVL in our series is slightly lower than the recent observations by Nobis et al [46], who published normative data from 19,700 UK Biobank cases and reported an acceleration of HVL after the age of 60 years with a 3.5% reduction between 70 and 75 years of age.…”

Mapping 3-year changes in gray matter and metabolism in Aβ-positive nondemented subjects

“…Our findings are consistent with previous reports of significantly faster GM atrophy in the precuneus of presymptomatic subjects with autosomal dominantly inherited AD (Benzinger et al, 2013) as well as preclinical sporadic AD (HC Aβ+) subjects (Chetelat et al, 2012; Mattsson et al, 2014; Nosheny et al, 2015). Moreover, Aβ-related longitudinal atrophy of the medial-temporal lobe (MTL) in HC subjects has been reported previously (Dickerson et al, 2011; Knopman et al, 2013; Villemagne et al, 2013).…”

Cross-Sectional and Longitudinal Hippocampal Atrophy, Not Cortical Thinning, Occurs in Amyloid-Negative, p-Tau-Positive, Older Adults With Non-Amyloid Pathology and Mild Cognitive Impairment

“…Most studies of the MCI population are performed in a mixed MCI population irrespective of amyloid status or only in amyloid-positive MCI participants. Our findings are very much in accordance with previous studies of amyloid-positive MCI participants, showing higher atrophy compared with controls (Huijbers et al, 2015 ; Nosheny et al, 2015 ; Jang et al, 2019 ). Cortical thinning has been most commonly reported in the medial temporal regions, parieto-occipital regions, and the frontal regions, also known as AD-vulnerable regions.…”

Hippocampal Volume Loss, Brain Amyloid Accumulation, and APOE Status in Cognitively Intact Elderly Subjects

“…The association between amyloid positivity and HVL in our cohort was at the level of a trend or was even nonsignificant depending on the regression models used. These observations are consistent with previous contributions indicating that amyloid burden may affect hippocampal integrity only in some vulnerable individuals, thereby accounting for a small percentage of HVL [42][43][44]. Our data parallel those in previous reports pointing to the relative independence between amyloid pathology and hippocampal structural changes in preclinical and prodromal AD cases.…”

“…HVL is known to be highly variable in the course of normal brain aging [41]. Consistent with recent contributions [42][43][44][45], the mean HVL in this series (4.5 years after inclusion) varied from 1 to 2.5%. The proportion of HVL in our series is slightly lower than the recent observations by Nobis et al [46], who published normative data from 19,700 UK Biobank cases and reported an acceleration of HVL after the age of 60 years with a 3.5% reduction between 70 and 75 years of age.…”

Mapping 3-year changes in gray matter and metabolism in Aβ-positive nondemented subjects

“…Our findings are consistent with previous reports of significantly faster GM atrophy in the precuneus of presymptomatic subjects with autosomal dominantly inherited AD (Benzinger et al, 2013) as well as preclinical sporadic AD (HC Aβ+) subjects (Chetelat et al, 2012; Mattsson et al, 2014; Nosheny et al, 2015). Moreover, Aβ-related longitudinal atrophy of the medial-temporal lobe (MTL) in HC subjects has been reported previously (Dickerson et al, 2011; Knopman et al, 2013; Villemagne et al, 2013).…”

Cross-Sectional and Longitudinal Hippocampal Atrophy, Not Cortical Thinning, Occurs in Amyloid-Negative, p-Tau-Positive, Older Adults With Non-Amyloid Pathology and Mild Cognitive Impairment

“…Most studies of the MCI population are performed in a mixed MCI population irrespective of amyloid status or only in amyloid-positive MCI participants. Our findings are very much in accordance with previous studies of amyloid-positive MCI participants, showing higher atrophy compared with controls (Huijbers et al, 2015 ; Nosheny et al, 2015 ; Jang et al, 2019 ). Cortical thinning has been most commonly reported in the medial temporal regions, parieto-occipital regions, and the frontal regions, also known as AD-vulnerable regions.…”

Hippocampal Volume Loss, Brain Amyloid Accumulation, and APOE Status in Cognitively Intact Elderly Subjects

“…The association between amyloid positivity and HVL in our cohort was at the level of a trend or was even nonsignificant depending on the regression models used. These observations are consistent with previous contributions indicating that amyloid burden may affect hippocampal integrity only in some vulnerable individuals, thereby accounting for a small percentage of HVL [42][43][44]. Our data parallel those in previous reports pointing to the relative independence between amyloid pathology and hippocampal structural changes in preclinical and prodromal AD cases.…”

“…HVL is known to be highly variable in the course of normal brain aging [41]. Consistent with recent contributions [42][43][44][45], the mean HVL in this series (4.5 years after inclusion) varied from 1 to 2.5%. The proportion of HVL in our series is slightly lower than the recent observations by Nobis et al [46], who published normative data from 19,700 UK Biobank cases and reported an acceleration of HVL after the age of 60 years with a 3.5% reduction between 70 and 75 years of age.…”

Mapping 3-year changes in gray matter and metabolism in Aβ-positive nondemented subjects

“…Our findings are consistent with previous reports of significantly faster GM atrophy in the precuneus of presymptomatic subjects with autosomal dominantly inherited AD (Benzinger et al, 2013) as well as preclinical sporadic AD (HC Aβ+) subjects (Chetelat et al, 2012; Mattsson et al, 2014; Nosheny et al, 2015). Moreover, Aβ-related longitudinal atrophy of the medial-temporal lobe (MTL) in HC subjects has been reported previously (Dickerson et al, 2011; Knopman et al, 2013; Villemagne et al, 2013).…”