Cardio-metabolic risk factors and cortical thickness in a neurologically healthy male population: results from the psychological, social and biological determinants of ill health (pSoBid) study

<p>Introduction: Cardio-metabolic risk factors have been associated with poor physical and mental health. Epidemiological studies have shown peripheral risk markers to be associated with poor cognitive functioning in normal healthy population and in disease. The aim of the study was to explore the relationship between cardio-metabolic risk factors and cortical thickness in a neurologically healthy middle aged population-based sample.</p> <p>Methods: T1-weighted MRI was used to create models of the cortex for calculation of regional cortical thickness in 40 adult males (average age = 50.96 years), selected from the PSOBID study. The relationship between cardio-vascular risk markers and cortical thickness across the whole brain, were examined using the general linear models. The relationship with various covariates of interest was explored.</p> <p>Results: Lipid fractions with greater triglyceride content (TAG, VLDL and LDL) were associated with greater cortical thickness pertaining to a number of regions in the brain. Greater C reactive protein (CRP) and Intercellular adhesion molecule (ICAM-1) levels were associated with cortical thinning pertaining to perisylvian regions in the left hemisphere. Smoking status and education status were significant covariates in the model.</p> <p>Conclusions: This exploratory study adds to a small body of existing literature increasingly showing a relationship between cardio-metabolic risk markers and regional cortical thickness involving a number of regions in the brain in a neurologically normal middle aged sample. A focused investigation of factors determining the inter-individual variations in regional cortical thickness in the adult brain could provide further clarity in our understanding of the relationship between cardio-metabolic factors and cortical structures.</p&gt

The Relationship between Cortical Blood Flow and Sub-Cortical White-Matter Health across the Adult Age Span

Degeneration of cerebral white matter is commonly observed in aging, and the associated degradation in neural connectivity contributes to cognitive decline in older adults. Vascular dysfunction has been implicated as a potential mechanism for general age-related neural tissue deterioration; however, no prior study has examined the direct relationship between cortical vascular health and subcortical white-matter integrity. In this work, we aimed to determine whether blood supply to the brain is associated with microstructural integrity of connective tissue, and whether such associations are regionally specific and mainly accounted for by aging. We examined the association between cerebral blood flow (CBF) in the cortical mantle, measured using arterial spin labeling (ASL), and subcortical white-matter integrity, measured using diffusion tensor imaging (DTI), in a group of healthy adults spanning early to late adulthood. We found cortical CBF to be significantly associated with white-matter integrity throughout the brain. In addition, these associations were only partially tied to aging, as they remained even when statistically controlling for age, and when restricting the analyses to a young subset of the sample. Furthermore, vascular risk was not a prominent determinant of these effects. These findings suggest that the overall blood supply to the brain is an important indicator of white-matter health in the normal range of variations amongst adults, and that the decline in CBF with advancing age may potentially exacerbate deterioration of the connective anatomy of the brain

the wearable devices opportunity

학위논문(박사) -- 서울대학교대학원 : 의과대학 의학과, 2022. 8. 김기웅.배경 및 목적: 치매로 인한 공공보건 부담이 가중됨에도 만족스러운 치료법은 부재한 현 상황은 치매 발병을 예방하거나 진행을 지연시키기 위해 인지저하 또는 치매 위험이 있는 사람들을 조기에 식별해야 할 필요를 더욱 부각시킨다. 최근 연구들은 보행 시 한발-한발 사이 보행인자들의 변동성을 의미하는 보행변이성이 인지 저하, 경도인지장애 및 치매의 위험과 밀접하게 관련되어 있다는 것을 보였다. 특히 웨어러블 센서를 통해 얻은 보행변이성은 감독이 없는 자연스러운 환경에서 더 오랜 기간 동안 측정값을 낮은 비용으로 얻을 수 있다는 실용적인 이점으로 인해 인지저하의 위험을 예측하는 유망한 디지털 바이오마커로 활용될 수 있다. 본 논문에서는, 신체에 부착한 단일 삼축가속계로 측정된 보행 변이성이 미래의 인지저하 위험을 예측하는 디지털 바이오마커로 사용될 수 있을지에 대해 연구하였다. 첫 번째 연구에서는 신체 부착 삼축가속계로 얻은 보행변이성이 정상인지를 가진 노인에서 미래 인지저하의 위험을 예측할 수 있는지를 조사했다. 두 번째 연구에서는 더 큰 표본 크기와 더 넓은 범위의 인지 기능을 가진 비치매 노인을 대상으로, 디지털 바이오마커로서 보행 변이성의 가능성을 이론적으로 뒷받침할 수 있는 신경기질에 대해 조사하였다. 또한, 높은 보행 변이성이 인지 기능 및 기억 기능에 관련된 것으로 밝혀진 뇌 영역에서의 얇아진 대뇌 피질 두께와 관련되어 있을 것이며, 그 영역이 보행-인지 사이의 연관성을 설명하는 공유 신경 기질에 해당할 것이라는 가설을 검증하였다. 방법: 연구 I에서 우리는 뇌허혈이나 파킨슨병이 없으면서, 지역사회에 거주하는, 인지적으로 정상인 노인 91명을 대상으로 4년 전향적 코호트 연구를 수행하였다. 체중심에 부착한 삼축가속계를 이용하여 보행변이성을 측정하였고, 경도인지장애에 관한 국제 워킹 그룹의 진단기준에 따라 경도인지 장애를 진단했다. 우리는 보행 변이성의 크기에 따라 연구대상자를 삼분위수로 분류하여, 보행변이성이 가장 큰 일분위 그룹과 나머지 그룹을 관찰하며 4년 동안의 경도인지장애의 발병을 추적하였다. 그룹간 경도인지장애 발병 위험 비교는 Log-rank test와 Kaplan-Meier 분석을 통해 수행했다. 경도인지장애 발병 위험비(Hazard Ratio, HR)는 연령, 성별, 교육수준, 누적질병평가척도 점수, GDS 점수, 아포지단백 E ε4 대립유전자 유무를 보정한 콕스 비례위험 회귀 분석을 사용하여 추정하였다. 연구 II에서 우리는 207명의 치매가 없는 노인을 대상으로, 보행변이성과 연관된 뇌 피질 및 피질 하 신경 구조, 보행변이성-인지기능의 공유신경기질을 횡단적으로 연구하였다. 자기공명영상에서 뇌 피질의 두께와 피질 하 구조물 부피를 구하여 보행변이성, 인지기능, 피질 두께와 피질 하 구조물 부피와의 연관성을 각각 조사했다. 또한 보행변이성과 인지기능 양쪽에 모두 유의한 연관성을 보이는 뇌영역의 피질 두께 또는 피질 하 구조물 부피가 실제로 보행변이성과 인지기능 관계에 미치는 매개효과를 분석하였다. 결과: 연구 I에서 보행변이성이 일분위에 속하는 노인들은 나머지 노인들에 비해서 4년 간 경도인지장애 발병 위험이 약 12배 더 높았다. (HR = 11.97, 95% CI = 1.29–111.37). 그러나 느린 보행 속도를 가진 노인들은 나머지 노인들과 비슷한 경도인지장애 발병위험을 보였다. (HR = 5.04, 95% CI = 0.53–48.18). 우리는 또한 보행변이성이 미래 인지저하를 예측하는 것에는 성별에 따른 차이가 유의하지 않다는 것을 밝혔다. 연구 대상자들을 보행변이성의 크기로 삼분위화 하는 과정에서의 역치효과 (threshold effect) 유무를 알아보기 위해, 보행변이성과 보행속도를 연속변수로 두고 분석하였을 때에도 보행변이성이 10% 증가할 때마다 인지저하의 위험이 1.5배 증가하는 반면 보행속도의 변화에 따라 인지감퇴 위험의 유의한 변화는 없었다. 연구 II에서 높은 보행변이성은 낮은 인지기능과 관련이 있었다. 우리는 높은 보행변이성이 광범위한 영역에서 대뇌피질 두께 감소와 연관이 있다는 것을 확인했다. 반면, 보행변이성은 피질 하 구조물의 부피와는 유의한 연관성을 보이지 않았다. 보행변이성과 유의한 상관관계를 보인 피질 클러스터 중 좌반구의 inferior temporal, entorhinal, parahippocampal, fusiform, and lingual을 포함하는 클러스터의 피질 두께는 전반적 인지기능 및 언어기억기능과 연관이 있었다. 결론 및 해석: 결론적으로 본 연구는, 신체부착 단일 삼축가속계로 측정한 보행변이성의 인지저하 위험 예측 디지털 바이오마커로서의 가능성에 근거를 제시하고 있다.Background and Objectives: Large public health burden of dementia and the absence of a cure highlight the need for early identification of those at risk for cognitive decline or dementia to prevent and/or delay the onset of dementia. Emerging evidence indicates gait variability, the fluctuation of a gait measure from one step to the next, strongly relate to the risk of cognitive decline, MCI and dementia. Gait variability obtain via wearable sensor is a promising digital biomarker for predicting risk of cognitive impairment due to its favorable practical advantages of being able to obtain measurements over a longer period of time under unsupervised real-world conditions at lower cost. In my thesis, I examine the possibility that gait variability measured by a single body-worn tri-axial accelerometer (TAA) can be used as a digital biomarker to predict future risk of cognitive decline. In the first study, I examined whether gait variability obtained by the body-worn TAA could predict future risk of cognitive decline in older people with normal cognition (NC). In the second study, I then identify neural substrates that theoretically support the potential of gait variability as a digital biomarker in older adults with larger sample size and broader range of cognitive function. Additionally, I hypothesized higher gait variability would be related to lower cortical thickness, especially in regions important for cognitive function and memory, and that these regions would represent a shared neural substrate for gait control and cognitive impairment. Methods: In the study I, we conducted 4-year prospective cohort study on 91 community-dwelling cognitively normal elderly individuals without cerebral ischemic burden or Parkinsonism. We evaluated gait speed and step time variability using a TAA placed on the center of body mass, and diagnosed mild cognitive impairment (MCI) according to the International Working Group on MCI. We performed Kaplan-Meier analysis with consecutive log-rank testing for MCI-free survival by cohort-specific tertiles of gait variability; hazard ratios (HR) of incident MCI were estimated using Cox proportional hazards regression analysis adjusted for age, sex, education level, Cumulative Illness Rating Scale score, GDS score, and presence of the apolipoprotein E ε4 allele. In the study II, we cross-sectionally investigated the cortical and subcortical neural structures associated with gait variability, and the shared neural substrates of gait variability and cognitive function in 207 non-demented older adults. We obtained the cortical thickness and subcortical volumes from the magnetic resonance images, and examined associations between gait variability, cognitive function, and cortical thickness and subcortical volumes. Finally, we analyzed the mediation effect of the cluster cortical thickness and subcortical volume which had a significant association with both gait variability and cognitive function on the association between gait variability and cognition. Results: In the study I, subjects with high gait variability showed about 12-fold higher risk of MCI (HR = 11.97, 95% CI = 1.29–111.37) than those with mid-to-low variability. However, those with slow gait speed showed comparable MCI risk to those with mid-to-high speed (HR = 5.04, 95% CI = 0.53– 48.18). We additionally found that no sex differences were found when assessing the ability of high gait variability to predict future cognitive decline. When we computed gait variability and gait speed as continuous variables to explore whether there are any threshold effects, the risk of incident cognitive decline increased 1.5 times per 10% increment of gait variability, whereas it did not change significantly with changes of gait speed. In the study II, higher gait variability was associated with lower cognitive functions. We found the widespread decrease in cortical thickness with increasing gait variability while there was no significant association with the volume of subcortical structures. Among the clusters that showed significant correlation with the gait variability, a cluster that included the inferior temporal, entorhinal, parahippocampal, fusiform, and lingual in left hemisphere was also associated with global cognitive function, and verbal memory function. Cortical thickness of the cluster explained 17% of the total effect of gait variability on global cognitive function measured by CERAD-TS. Interpretation: Gait variability measured by a single body-worn TAA could be a novel digital biomarker of risk of cognitive decline that could be used repeatedly and frequently and at low cost to test risk of individuals without clinical evidence of cognitive impairments.I Introduction 10 1. Study background 11 2. Purpose of research 16 II Methods 18 1. Study 1: Can gait variability predict the risk of cognitive decline in cognitively normal elderly? 19 1.1. Study population 19 1.2. Clinical assessments 20 1.3. Gait Assessments 22 1.4. Statistical analysis 23 2. Study 2: Shared Neural Substrates between Gait Variability-Cognitive Function 24 2.1. Study population 24 2.2. Assessments of cognition and medical conditions 25 2.3. Gait assessments 26 2.4. Magnetic resonance imaging (MRI) acquisition and preprocessing 27 2.5. Statistical analyses 28 III Results 32 1. Study 1: Can gait variability predict the risk of cognitive decline in cognitively normal elderly? 33 1.1. Association of gait variability and gait speed status with the risk of MCI 34 2. Study 2: Shared Neural Substrates between Gait Variability-Cognitive Function 35 IV Discussion 38 [Figure 1] Risk of incident mild cognitive impairment over 4 years stratified by gait speed (a) and variability (b) by log-rank test 49 [Figure 2] Cortical thickness and gait variability in non-demented older adults 50 [Figure 3] Cortical thickness of LH1 cluster mediates effect of gait variability on CERAD-TS (a) and VMS (b) 51 [Table 1] Demographic, clinical, cognitive function, and gait characteristics of the subjects 52 [Table 2] Prediction of mild cognitive impairment in cognitively normal elderly individuals 54 [Table 3] Characteristics of participants 55 [Table 4] Vertex-Wise Analyses of Gait Variability and Cortical Thickness 56 [Table 5] Regression Analyses of Gait Variability and Cortical Thickness 57 [Table 6] Associations between Cortical Regions related with Gait Variability and Cognitive Function 58 Bibliography 59 감사의 글 66 초 록 67박

Rumination and executive dysfunction: Risk factors for vascular depression

Introduction: The widely-supported vascular depression hypothesis is underspecified with respect to cognitive mechanisms by which high cerebrovascular burden (CVB) and neuropathology relate to depressive symptoms. Integration of the vascular depression hypothesis with the CaR-FA-X model, a framework of affect regulation mechanisms, suggest that Rumination (R) and executive dysfunction (X) may increase due to altered recruitment of the dorsolateral prefrontal cortex resulting from high CVB and underlying neuropathology. This process would contribute to depressive symptomatology among older adults with high CVB. The progression of examined hypotheses included mediation models examining mechanistic relationships between predictors (CVB, DLPFC activation), cognitive correlates (rumination, executive functioning), and affective outcomes (depressive symptoms). Method: A sample of 52 community-dwelling, stroke-free, individuals over the age of 70, without history of severe mental illness, dementia, or severe cognitive impairment, completed the Ruminative Responses Scale, provided self-reported cerebrovascular burden data (cardiac disease, hypertension, diabetes, high cholesterol), and completed executive function tasks (Stroop, Flanker) while their hemodynamic response was measured using fNIRS. The Geriatric Depression Scale was used to assess depressive symptomatology. Prefrontal cortical recruitment was assessed using functional near-infrared spectroscopy (fNIRS). Results: A progression of conventional and bootstrapped regression-based models broadly supported relationships between CVB and depressive symptoms, but not between DLPFC activation and depressive symptoms. No mechanistic relationships were found, with respect to analyses testing prospective cognitive mediators. Conclusions: Primary findings from this study indicate that cerebrovascular burden predicts depressive symptomatology among older adults and is related to a reduction in inhibitory control ability. Further, these findings inform CVB measurement and mental health implications of contrasting approaches to CVB measurement. A primary contribution of this thesis is that results appear to support utilization of fNIRS, a low-cost and accessible neuroimaging paradigm, for the study of lateralized cognition among older adults

Moderating Effect of Cortical Thickness on BOLD Signal Variability Age-Related Changes

The time course of neuroanatomical structural and functional measures across the lifespan is commonly reported in association with aging. Blood oxygen-level dependent signal variability, estimated using the standard deviation of the signal, or “BOLDSD,” is an emerging metric of variability in neural processing, and has been shown to be positively correlated with cognitive flexibility. Generally, BOLDSD is reported to decrease with aging, and is thought to reflect age-related cognitive decline. Additionally, it is well established that normative aging is associated with structural changes in brain regions, and that these predict functional decline in various cognitive domains. Nevertheless, the interaction between alterations in cortical morphology and BOLDSD changes has not been modeled quantitatively. The objective of the current study was to investigate the influence of cortical morphology metrics [i.e., cortical thickness (CT), gray matter (GM) volume, and cortical area (CA)] on age-related BOLDSD changes by treating these cortical morphology metrics as possible physiological confounds using linear mixed models. We studied these metrics in 28 healthy older subjects scanned twice at approximately 2.5 years interval. Results show that BOLDSD is confounded by cortical morphology metrics. Respectively, changes in CT but not GM volume nor CA, show a significant interaction with BOLDSD alterations. Our study highlights that CT changes should be considered when evaluating BOLDSD alternations in the lifespan

Neuroprotective Effects of Cardiorespiratory Fitness on White Matter Integrity and Cognition Across the Adult Lifespan

Objective: Cardiorespiratory fitness (CRF) is associated with decreased risk for cognitive decline. Accumulating evidence has linked CRF to more conserved white matter (WM) integrity and better cognitive performance in older adults. Additional research is needed to determine: (1) which WM tracts are most strongly related to CRF, (2) whether CRF-related benefits on WM translate to enhanced executive functioning (EF), and (3) if the neuroprotective effects of CRF are age-dependent. This study aimed to evaluate CRF as an intervention for modulating decreased WM integrity and EF in aging. Method: Participants were community-dwelling adults (N = 499; ages 20-85) from the open-access Nathan Kline Institute – Rockland Sample (NKIRS) with CRF (bike test), self-report of physical activity, diffusion tensor imaging (DTI), and EF data. Mixed-effect modeling tested the interaction between CRF and age on WM integrity (global and local microstructure). Significant WM tracts were retained for structural equation modeling to determine whether enhanced microstructure mediated a positive relationship between CRF and EF. Results: Among older participants (age 60), CRF was significantly related to stronger whole-brain (z-score slope = 0.11) and local WM integrity within five tracts (z-score slope range = 0.14 – 0.20). In support of the age-dependent hypothesis, the CRF–WM relationship was comparably weaker (z-score slopes 0.11) and more limited (one WM tract) in younger adults. CRF was more consistently related to WM than self-report of physical activity. Although CRF was linked to enhanced WM integrity, its potential benefits on EF were not directly observed. Conclusion: The findings highlight the importance of positive lifestyle factors, such as physical activity, in maintaining brain health in senescence. CRF may selectively preserve a collection of anterior and posterior WM connections related to visuomotor function

Autonomic function in amnestic and non-amnestic mild cognitive impairment : spectral heart rate variability analysis provides evidence for a brain–heart axis

Mild cognitive impairment (MCI) is a heterogeneous syndrome with two main clinical subtypes, amnestic (aMCI) and non-amnestic (naMCI). The analysis of heart rate variability (HRV) is a tool to assess autonomic function. Cognitive and autonomic processes are linked via the central autonomic network. Autonomic dysfunction entails several adverse outcomes. However, very few studies have investigated autonomic function in MCI and none have considered MCI subtypes or the relationship of HRV indices with different cognitive domains and structural brain damage. We assessed autonomic function during an active orthostatic challenge in 253 oupatients aged\u2009 65\u200965, [n\u2009=\u200982 aMCI, n\u2009=\u200993 naMCI, n\u2009=\u200978 cognitively normal (CN), neuropsychologically tested] with power spectral analysis of HRV. We used visual rating scales to grade cerebrovascular burden and hippocampal/insular atrophy (HA/IA) on neuroimaging. Only aMCI showed a blunted response to orthostasis. Postural changes in normalised low frequency (LF) power and in the LF to high frequency ratio correlated with a memory test (positively) and HA/IA (negatively) in aMCI, and with attention/executive function tests (negatively) and cerebrovascular burden (positively) in naMCI. These results substantiate the view that the ANS is differentially impaired in aMCI and naMCI, consistently with the neuroanatomic substrate of Alzheimer's and small-vessel subcortical ischaemic disease

Endothelial Function Is Associated with White Matter Microstructure and Executive Function in Older Adults

Age-related declines in endothelial function can lead to cognitive decline. However, little is known about the relationships between endothelial function and specific neurocognitive functions. This study explored the relationship between measures of endothelial function (reactive hyperemia index; RHI), white matter (WM) health (fractional anisotropy, FA, and WM hyperintensity volume, WMH), and executive function (Trail Making Test (TMT); Trail B - Trail A). Participants were 36 older adults between the ages of 59 and 69 (mean age = 63.89 years, SD = 2.94). WMH volume showed no relationship with RHI or executive function. However, there was a positive relationship between RHI and FA in the genu and body of the corpus callosum. In addition, higher RHI and FA were each associated with better executive task performance. Tractography was used to localize the WM tracts associated with RHI to specific portions of cortex. Results indicated that the RHI-FA relationship observed in the corpus callosum primarily involved tracts interconnecting frontal regions, including the superior frontal gyrus (SFG) and frontopolar cortex, linked with executive function. These findings suggest that superior endothelial function may help to attenuate age-related declines in WM microstructure in portions of the corpus callosum that interconnect prefrontal brain regions involved in executive function