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Deviations in Hippocampal Subregion Associated With Cognitive and Physical Frailty in Older Adults With Cognitive Frailty

16 Sep 2020-

TL;DR: Significant volume decrease occurs in hippocampal subregions of older adults with cognitive frailty, and these changes are correlated with cognitive decline and physical frailty.
Abstract: Background The hippocampus is a complex, heterogeneous structure that is composed of widely different and interacting subregions. Atrophy of these subregions has been implicated in a variety of neurodegenerative diseases. Cognitive frailty is a kind of neurodegenerative disease with unclear neuropathological changes. The aim of this study was to explore the changes in hippocampal subregions in older adults with cognitive frailty and the relationship between subregions and cognitive decline as well as physical frailty.Methods Twenty-six older adults with cognitive frailty and 26 matched healthy controls were included in this study. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA) scale (Fuzhou version) and Wechsler's Memory Scale, while physical frailty was tested with the Chinese version of the Edmonton Frailty Scale (EFS) and grip strength. The volume of the hippocampal subregions was measured with structural brain magnetic resonance imaging. Partial correlation analysis was carried out between the volumes of hippocampal subregions and MoCA scores, Wechsler’s Memory Quotient and physical frailty indexes.Results A significant volume decrease was found in six hippocampal subregions, including the bilateral presubiculum, the left parasubiculum, molecular layer of the HP, and HATA, and the right CA1 area, in older adults with cognitive frailty (P<0.05/12), while the proportion of brain parenchyma and total number of white matter fibers were lower than those in the healthy controls (P<0.05). Positive correlations were found between Wechsler’s Memory Quotient and the size of the left molecular layer of the HP and HATA and the right presubiculum (P<0.05). The sizes of the left presubiculum, molecular of the layer HP, and HATA and right CA1 and presubiculum were found to be positively correlated with MoCA score (P<0.05). The sizes of the left parasubiculum, molecular layer of the HP and HATA were found to be negatively correlated with the physical frailty index (P<0.05).Conclusion Significant volume decrease occurs in hippocampal subregions of older adults with cognitive frailty, and these changes are correlated with cognitive decline and physical frailty. Therefore, the atrophy of hippocampal subregions could participate in the pathological progression of cognitive frailty.
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Deviations in Hippocampal Subregion Associated
With Cognitive and Physical Frailty in Older Adults
With Cognitive Frailty
Mingyue Wan
Fujian University of Traditional Chinese Medicine
Yu Ye
Fujian University of Traditional Chinese Medicine
Huiying Lin
Fujian University of Traditional Chinese Medicine
Ying Xu
Fujian University of Traditional Chinese Medicine
Shengxiang Liang
Fujian University of Traditional Chinese Medicine
Rui Xia
Fujian University of Traditional Chinese Medicine
Jianquan He
Fujian University of Traditional Chinese Medicine
Pingting Qiu
Fujian University of Traditional Chinese Medicine
Chengwu Huang
Fujian University of Traditional Chinese Medicine
Jing Tao
Fujian University of Traditional Chinese Medicine
Lidian Chen
Fujian University of Traditional Chinese Medicine
Guohua Zheng ( 1181256002@fjtcm.edu.cn )
College of Nursing and Health Management, Shanghai University of Medicine & Health Sciences,
Shanghai 201318, China.
Research
Keywords: Cognitive frailty, Hippocampal subregion, Volume, Diffusion tensor imaging, Correlation
Posted Date: September 16th, 2020

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DOI: https://doi.org/10.21203/rs.3.rs-74177/v1
License: This work is licensed under a Creative Commons Attribution 4.0 International License. 
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Abstract
Background The hippocampus is a complex, heterogeneous structure that is composed of widely
different and interacting subregions. Atrophy of these subregions has been implicated in a variety of
neurodegenerative diseases. Cognitive frailty is a kind of neurodegenerative disease with unclear
neuropathological changes. The aim of this study was to explore the changes in hippocampal subregions
in older adults with cognitive frailty and the relationship between subregions and cognitive decline as well
as physical frailty.
Methods Twenty-six older adults with cognitive frailty and 26 matched healthy controls were included in
this study. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA) scale
(Fuzhou version) and Wechsler's Memory Scale, while physical frailty was tested with the Chinese version
of the Edmonton Frailty Scale (EFS) and grip strength. The volume of the hippocampal subregions was
measured with structural brain magnetic resonance imaging. Partial correlation analysis was carried out
between the volumes of hippocampal subregions and MoCA scores, Wechsler’s Memory Quotient and
physical frailty indexes.
Results A signicant volume decrease was found in six hippocampal subregions, including the bilateral
presubiculum, the left parasubiculum, molecular layer of the HP, and HATA, and the right CA1 area, in
older adults with cognitive frailty (P<0.05/12), while the proportion of brain parenchyma and total number
of white matterbers were lower than those in the healthy controls (
P
<0.05). Positive correlations were
found between Wechslers Memory Quotient and the size of the left molecular layer of the HP and HATA
and the right presubiculum (
P
<0.05). The sizes of the left presubiculum, molecular of the layer HP, and
HATA and right CA1 and presubiculum were found to be positively correlated with MoCA score (
P
<0.05).
The sizes of the left parasubiculum, molecular layer of the HP and HATA were found to be negatively
correlated with the physical frailty index (
P
<0.05).
Conclusion Signicant volume decrease occurs in hippocampal subregions of older adults with cognitive
frailty, and these changes are correlated with cognitive decline and physical frailty. Therefore, the atrophy
of hippocampal subregions could participate in the pathological progression of cognitive frailty.
Introduction
Cognitive frailty (CF) is a major subtype of frailty. According to the International Academy on Nutrition
and Aging (I.A.N.A.) and the International Association of Gerontology and Geriatrics (I.A.G.G.), in 2013, CF
was rst dened as a clinical syndrome characterized by physical frailty and cognitive impairment
among older adults, excluding Alzheimer's disease and other dementias[1]. Epidemiological surveys
estimated the prevalence rate of CF to be 3–9.8% in the general older adult population, whereas the gure
was much higher, 10.7–40%, in the clinical setting [2–3]. CF can accelerate cognitive impairment and
physical frailty in older adults, is associated with a decline in activities of daily living and quality of life,
and increases the risk of dementia, falls, disability and death[4]. As human life expectancy continues to

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increase, the prevalence of cognitive frailty is rapidly increasing and has become one of the biggest
health threats in the 21st century[5]. Therefore, it is important for early intervention to nd an effective
brain biomarker that can enable early identication of older adults with CF.
Previous studies found that the hippocampus is the core brain area related to cognition, but it is not a
unied brain region; rather it is composed of several subregions with specic histological features, and
distinct pathways affect its overall function[6–7]. Therefore, the function of the hippocampus depends
on its own internal structures, such as hippocampal subelds, and the connections of its surrounding
structures with other parts of the brain[8]. For example, a recent work showed that the anterior
hippocampus contributed to global memory, perception, imagination and recall of scenes and events[9].
The posterior hippocampus was found to support ne and perceptual detailed memory [10]. The head of
the hippocampus is related to logical memory, while the body and tail of the hippocampus are related to
visual memory[11]. The cornu Ammonis subeld 1 (CA1) of the hippocampus is connected to the
posterior cingulate cortex, which can regulate episodic memory[12]. Therefore, the distinct hippocampal
subregions are related to different types of cognition. However, its mechanism in CF remains unclear.
Previous research has shown that physical decline in the process of aging may be at least partly due to
damage to the brain or nerve function, not just disorders of skeletal muscle, and the hippocampus might
be involved in the regulation of human body functions[13, 14]. It is well known that the hippocampus is
devoted to balance regulation and sensory motor integration[14], while the hippocampus body and
anterior cingulate gyrus are involved in memory and executive function[15]. Moreover, a reduced integrity
of the gray matter in these two regions was positively correlated with greater stride variability in elderly
adults, which indicates the role of cognitive function in motor control[16]. A positive correlation between
the left hippocampus volume, especially of the left CA1, CA2 and subiculum, among elderly adults and
the balance composite score was also observed[17]. Elderly adults with a strong sense of fatigue have a
smaller hippocampal volume than normal elderly adults[18]. Therefore, the hippocampus or its
subregions might contribute to the process of both cognitive and physical decline. We speculated that the
hippocampus or its subregions play an important role in the pathogenesis of CF. To address this
hypothesis, we performed high-resolution structural MRI scans in a group of older adults with CF as well
as in controls. We used volumetry analysis to assess different aspects of the hippocampus and
hippocampal subregions. The above indicators as well as behavioral indicators were subjected to
correlation analysis to clarify the relationship. The whole brain index evaluation included analysis of
cortical thickness, the number of white matter bers in the whole brain and the proportion of brain
parenchyma.
Materials And Methods
Participants
This cross-sectional study recruited 26 older adults with CF and 26 matched healthy controls between
April 2019 and September 2019 from communities in Fuzhou City, Fujian Province, China. All 52

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participants included in this study participated in complete assessment scale and neuroimaging data
collection. This study was approved by the ethics committee of the Second People's Hospital Aliated
with Fujian University of Traditional Chinese Medicine. Written informed consent was obtained from all
participants before participation.
All CF participants met the following inclusion criteria: Chinese version of Edmonton Frailty Scale (EFS)
score 5 points; Fuzhou version of the MoCA score 26 scores; Clinical Dementia Rating (CDR) Scale
score = 0.5 (i.e., just mild cognitive impairment) and age 60years. The inclusion criteria for the age- and
education-matched controls were an EFS score < 5; a Fuzhou version of the MoCA score > 26; and a CDR
Scale score = 0.
Individuals were excluded when they met one of the following conditions: history of mental illness (such
as personality disorder, schizophrenia, etc.); serious depression (Becker depression scale score > 10); mild
dementia and above (CDR Scale score > 0.5); history of alcohol or drug abuse; use of drugs that inuence
cognitive function; serious organ failure, cerebral hemorrhage, sequelae of cerebral infarction;
unsuitability for MRI scanning (such as xed metal dentures, pacemakers, etc.); and participation in
another clinical trial.
Cognitive and physical frailty assessment
Global cognitive ability and memory were evaluated by using the Fuzhou version of the MoCA and
Wechsler’s Memory Scale. MoCA scores range from 0–30, and a higher score indicates better cognitive
function; scores lower than 26 points are considered to represent mild cognitive impairment[19].
Wechsler’s Memory Quotient ranges from 51 to 150, with higher scores indicating better memory.
Physical frailty was assessed through the Chinese version of the Edmonton Frailty Scale (EFS) and the
grip strength test.
MRI data acquisition
All participants underwent T1 and DTI imaging on a Siemens Prisma 3.0T magnetic resonance scanner
(Siemens Medical System, Erlangen, Germany) at Fujian Province Rehabilitation Hospital. The
parameters of T1 imaging were as follows: repetition time (TR) = 2300ms, echo time (TE) = 2.27ms, ip
angle = 8°, slice thickness = 1.0mm, eld of view (FOV) = 250 mm ×250mm, matrix = 256 × 256, voxel
size = 0.98 × 0.98 × 1 mm
3
, and number of slices =160. For DTI, the parameters were as follows: TR = 
8000ms, TE = 64ms, FOV = 224 mm ×224mm, slice thickness = 2.0mm, gap = 0mm, slice number = 75,
and slice order = interleaved.
Imaging Processing
All T1-weighted images were processed by publicly available FreeSurfer software (Version 6.0.0,
http://www.freesurfer.net/) using the default settings. Before data preprocessing, image format
conversion and image quality assessment were needed. Then, the command “recon-all” in FreeSurfer
6.0.0 was used for volumetric segmentation, specically including Talairach transformation, intensity
normalization, skull stripping, volumetric registration, segmentation of gray and white matter and

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Mingyue Wan1, Yu Ye2, Huiying Lin2, Ying Xu2  +8 moreInstitutions (2)
Abstract: Background Cognitive frailty is a particular state of cognitive vulnerability toward dementia with neuropathological hallmarks. The hippocampus is a complex, heterogeneous structure closely relates to the cognitive impairment in elderly which is composed of 12 subregions. Atrophy of these subregions has been implicated in a variety of neurodegenerative diseases. The aim of this study was to explore the changes in hippocampal subregions in older adults with cognitive frailty and the relationship between subregions and cognitive impairment as well as physical frailty. Methods Twenty-six older adults with cognitive frailty and 26 matched healthy controls were included in this study. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA) scale (Fuzhou version) and Wechsler Memory Scale-Revised Chinese version (WMS-RC), while physical frailty was tested with the Chinese version of the Edmonton Frailty Scale (EFS) and grip strength. The volume of the hippocampal subregions was measured with structural brain magnetic resonance imaging. Partial correlation analysis was carried out between the volumes of hippocampal subregions and MoCA scores, Wechsler's Memory Quotient and physical frailty indexes. Results A significant volume decrease was found in six hippocampal subregions, including the bilateral presubiculum, the left parasubiculum, molecular layer of the hippocampus proper (molecular layer of the HP), and hippocampal amygdala transition area (HATA), and the right cornu ammonis subfield 1 (CA1) area, in older adults with cognitive frailty, while the proportion of brain parenchyma and total number of white matter fibers were lower than those in the healthy controls. Positive correlations were found between Wechsler's Memory Quotient and the size of the left molecular layer of the HP and HATA and the right presubiculum. The sizes of the left presubiculum, molecular of the layer HP, and HATA and right CA1 and presubiculum were found to be positively correlated with MoCA score. The sizes of the left parasubiculum, molecular layer of the HP and HATA were found to be negatively correlated with the physical frailty index. Conclusion Significant volume decrease occurs in hippocampal subregions of older adults with cognitive frailty, and these changes are correlated with cognitive impairment and physical frailty. Therefore, the atrophy of hippocampal subregions could participate in the pathological progression of cognitive frailty.

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