Causal structure discovery identifies risk factors and early brain markers related to evolution of white matter hyperintensities

Shen, Xinpeng; Raghavan, Sheelakumari; Przybelski, Scott A.; Lesnick, Timothy G.; Ma, Sisi; Reid, Robert I.; Graff‐Radford, Jonathan; Mielke, Michelle M.; Knopman, David S.; Petersen, Ronald C.; Jack, Clifford R.; Simon, György; Vemuri, Prashanthi

doi:10.1016/j.nicl.2022.103077

Cited by 12 publications

(12 citation statements)

References 79 publications

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“…Together, these findings extend past evidence from us 20,21,37 and others, 12,45 suggesting an association between modifiable risk factors (hypertension, diabetes, hyperlipidemia, obesity, and smoking status) and reduced WM integrity of the genu of the corpus callosum before overt WMH. 37,46,47 of WMH in association with VRFs. 37,38,48,49 It might be attributed to underlying mechanisms such as vascular risk-induced hypoperfusion, altered cerebrovascular reactivity, and increased blood-brain barrier permeability.…”

Section: Vascular Health and Wm Damagesupporting

confidence: 88%

“…We categorized participants years. 37,38 Further, the predictors that drive SVD changes in the older age strata may differ from those in the younger groups because SVD is highly prevalent in those >80 years of age.…”

Section: Discussionmentioning

confidence: 99%

“…37,46,47 of WMH in association with VRFs. 37,38,48,49 It might be attributed to underlying mechanisms such as vascular risk-induced hypoperfusion, altered cerebrovascular reactivity, and increased blood-brain barrier permeability. 50 Furthermore, we found slower progression of WMH in association with CMC at the eighth decade of life, which is consistent with previous findings.…”

Section: Vascular Health and Wm Damagementioning

confidence: 97%

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Vascular risk, gait, behavioral, and plasma indicators of VCID

Raghavan,

Przybelski,

Lesnick

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONCost‐effective screening tools for vascular contributions to cognitive impairment and dementia (VCID) has significant implications. We evaluated non‐imaging indicators of VCID using magnetic resonance imaging (MRI)‐measured white matter (WM) damage and hypothesized that these indicators differ based on age.METHODSIn 745 participants from the Mayo Clinic Study of Aging (≥50 years of age) with serial WM assessments from diffusion MRI and fluid‐attenuated inversion recovery (FLAIR)‐MRI, we examined associations between baseline non‐imaging indicators (demographics, vascular risk factors [VRFs], gait, behavioral, plasma glial fibrillary acidic protein [GFAP], and plasma neurofilament light chain [NfL]) and WM damage across three age tertiles.RESULTSVRFs and gait were associated with diffusion changes even in low age strata. All measures (VRFs, gait, behavioral, plasma GFAP, plasma NfL) were associated with white matter hyperintensities (WMHs) but mainly in intermediate and high age strata.DISCUSSIONNon‐imaging indicators of VCID were related to WM damage and may aid in screening participants and assessing outcomes for VCID.HIGHLIGHTS Non‐imaging indicators of VCID can aid in prediction of MRI‐measured WM damage but their importance differed by age. Vascular risk and gait measures were associated with early VCID changes measured using diffusion MRI. Plasma markers explained variability in WMH across age strata. Most non‐imaging measures explained variability in WMH and vascular WM scores in intermediate and older age groups. The framework developed here can be used to evaluate new non‐imaging VCID indicators proposed in the future.

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Section: Vascular Health and Wm Damagesupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Vascular Health and Wm Damagementioning

confidence: 97%

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Vascular risk, gait, behavioral, and plasma indicators of VCID

Raghavan,

Przybelski,

Lesnick

et al. 2023

Alzheimer's & Dementia

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“…Although nonspecific, we have previously shown that genu FA can be an early indicator of CVD because of worsening systemic vascular health. 7,30…”

Section: Methodsmentioning

confidence: 99%

Association of Polysomnographic Sleep Parameters With Neuroimaging Biomarkers of Cerebrovascular Disease in Older Adults With Sleep Apnea

Carvalho,

McCarter,

St Louis

et al. 2023

Neurology

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Background and Objectives:Our objective was to determine whether polysomnographic (PSG) sleep parameters are associated with neuroimaging biomarkers of cerebrovascular disease (CVD) related to white matter integrity in older adults with obstructive sleep apnea (OSA).Methods:From the population-based Mayo Clinic Study of Aging, we identified participants without dementia who underwent at least one brain MRI and PSG. We quantified two CVD biomarkers: white matter hyperintensities (WMH) from FLAIR-MRI and fractional anisotropy of the genu of the corpus callosum (genu FA) from diffusion MRI. For this cross-sectional analysis, we fit linear models to assess associations between PSG parameters (N1%, N3% [slow-wave sleep], mean oxyhemoglobin saturation, and log of apnea-hypopnea index [AHI]) and CVD biomarkers (log of WMH and log of genu FA), respectively, while adjusting for age (at MRI), sex, APOε4 status, composite cardiovascular and metabolic conditions (CMC) score, REM stage percentage, sleep duration, and interval between MRI and PSG.Results:We included 140 participants with FLAIR-MRI (of which 103 had additional diffusion MRI). The mean ± s.d. age was 72.7 ± 9.6 years old at MRI with nearly 60% being men. The absolute median (IQR) interval between MRI and PSG was 1.74 (0.9 – 3.2) years. 90.7% were cognitively unimpaired during both assessments. For every 10-point decrease in N3%, there was a 0.058 (95% CI 0.006 to 0.111, p=0.030) increase in the log of WMH and 0.006 decrease (95% CI -0.012 to -0.0002, p=0.042) in the log of genu FA. After matching for age, sex, and N3%, participants with severe OSA had higher WMH (median [IQR] 0.007 [0.005 to 0.015] vs. 0.006 [0.003 to 0.009], p=0.042) and lower genu FA (median [IQR] 0.57 [0.55 to 0.63] vs. 0.63 [0.58 to 0.65], p=0.007), when compared with those with mild/moderate OSA.Discussion:We found that reduced slow-wave sleep and severe OSA were associated with higher burden of white matter abnormalities in predominantly cognitively unimpaired older adults, which may contribute to greater risk of cognitive impairment, dementia, and stroke. Our study supports the association between sleep depth/fragmentation and intermittent hypoxia and CVD biomarkers. Longitudinal studies are required to assess causation.

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“…CDS methods have yielded important advances in medical fields such as cancer, diabetes, rheumatic disease, and infectious diseases (102)(103)(104)(105)(106)(107)(108)(109)(110). Since 2016, a series of published studies have demonstrated their applicability to mental disorders with data sets of modest size, containing variables typically measured in longitudinal risk factor research studies on mental disorder outcomes.…”

Section: Track Record Of Causal Data Science Methods For Determining ...mentioning

confidence: 99%

Mental health progress requires causal diagnostic nosology and scalable causal discovery

Saxe

Bickman

et al. 2022

Front. Psychiatry

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Nine hundred and seventy million individuals across the globe are estimated to carry the burden of a mental disorder. Limited progress has been achieved in alleviating this burden over decades of effort, compared to progress achieved for many other medical disorders. Progress on outcome improvement for all medical disorders, including mental disorders, requires research capable of discovering causality at sufficient scale and speed, and a diagnostic nosology capable of encoding the causal knowledge that is discovered. Accordingly, the field’s guiding paradigm limits progress by maintaining: (a) a diagnostic nosology (DSM-5) with a profound lack of causality; (b) a misalignment between mental health etiologic research and nosology; (c) an over-reliance on clinical trials beyond their capabilities; and (d) a limited adoption of newer methods capable of discovering the complex etiology of mental disorders. We detail feasible directions forward, to achieve greater levels of progress on improving outcomes for mental disorders, by: (a) the discovery of knowledge on the complex etiology of mental disorders with application of Causal Data Science methods; and (b) the encoding of the etiological knowledge that is discovered within a causal diagnostic system for mental disorders.

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Causal structure discovery identifies risk factors and early brain markers related to evolution of white matter hyperintensities

Cited by 12 publications

References 79 publications

Vascular risk, gait, behavioral, and plasma indicators of VCID

Vascular risk, gait, behavioral, and plasma indicators of VCID

Association of Polysomnographic Sleep Parameters With Neuroimaging Biomarkers of Cerebrovascular Disease in Older Adults With Sleep Apnea

Mental health progress requires causal diagnostic nosology and scalable causal discovery

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