Higher White Matter Hyperintensity Volume Research Articles

Neuroimaging, clinical and life course correlates of normal-appearing white matter integrity in 70-year-olds.

We investigate associations between normal-appearing white matter microstructural integrity in cognitively normal ∼70-year-olds and concurrently measured brain health and cognition, demographics, genetics and life course cardiovascular health. Participants born in the same week in March 1946 (British 1946 birth cohort) underwent PET-MRI around age 70. Mean standardized normal-appearing white matter integrity metrics (fractional anisotropy, mean diffusivity, neurite density index and orientation dispersion index) were derived from diffusion MRI. Linear regression was used to test associations between normal-appearing white matter metrics and (i) concurrent measures, including whole brain volume, white matter hyperintensity volume, PET amyloid and cognition; (ii) the influence of demographic and genetic predictors, including sex, childhood cognition, education, socio-economic position and genetic risk for Alzheimer's disease (APOE-ɛ4); (iii) systolic and diastolic blood pressure and cardiovascular health (Framingham Heart Study Cardiovascular Risk Score) across adulthood. Sex interactions were tested. Statistical significance included false discovery rate correction (5%). Three hundred and sixty-two participants met inclusion criteria (mean age 70, 49% female). Higher white matter hyperintensity volume was associated with lower fractional anisotropy [b = -0.09 (95% confidence interval: -0.11, -0.06), P < 0.01], neurite density index [b = -0.17 (-0.22, -0.12), P < 0.01] and higher mean diffusivity [b = 0.14 (-0.10, -0.17), P < 0.01]; amyloid (in men) was associated with lower fractional anisotropy [b = -0.04 (-0.08, -0.01), P = 0.03)] and higher mean diffusivity [b = 0.06 (0.01, 0.11), P = 0.02]. Framingham Heart Study Cardiovascular Risk Score in later-life (age 69) was associated with normal-appearing white matter {lower fractional anisotropy [b = -0.06 (-0.09, -0.02) P < 0.01], neurite density index [b = -0.10 (-0.17, -0.03), P < 0.01] and higher mean diffusivity [b = 0.09 (0.04, 0.14), P < 0.01]}. Significant sex interactions (P < 0.05) emerged for midlife cardiovascular health (age 53) and normal-appearing white matter at 70: marginal effect plots demonstrated, in women only, normal-appearing white matter was associated with higher midlife Framingham Heart Study Cardiovascular Risk Score (lower fractional anisotropy and neurite density index), midlife systolic (lower fractional anisotropy, neurite density index and higher mean diffusivity) and diastolic (lower fractional anisotropy and neurite density index) blood pressure and greater blood pressure change between 43 and 53 years (lower fractional anisotropy and neurite density index), independently of white matter hyperintensity volume. In summary, poorer normal-appearing white matter microstructural integrity in ∼70-year-olds was associated with measures of cerebral small vessel disease, amyloid (in males) and later-life cardiovascular health, demonstrating how normal-appearing white matter can provide additional information to overt white matter disease. Our findings further show that greater 'midlife' cardiovascular risk and higher blood pressure were associated with poorer normal-appearing white matter microstructural integrity in females only, suggesting that women's brains may be more susceptible to the effects of midlife blood pressure and cardiovascular health.

Independent associations of plasma Aβ42 and plasma neurofilament light with white matter hyperintensity volume in non‐demented older individuals

AbstractBackgroundPlasma biomarkers have potential to capture features of Alzheimer’s disease (AD)‐related pathophysiology, but less is known about how they might associate with an imaging measure of cerebral small vessel disease (cSVD). The present study examined independent and combined associations of plasma markers of AD pathology (Aβ42, P‐tau181), axonal damage (neurofilament light [NfL]), and astrocytic activation (glial fibrillary acidic protein [GFAP]) with white matter hyperintensity (WMH) volume in adults without dementia.MethodPlasma Aβ42, P‐tau181, NfL, and GFAP (Quanterix Simoa) were measured in 151 older adults without dementia (124 cognitively unimpaired, 27 mild cognitive impairment; aged 52 ‐ 91, 57% female, 95% non‐Hispanic white) who underwent MRI with T2‐weighted FLAIR. Controlling for age, sex, APOE genotype, and intracranial volume, linear regressions first examined WMH volume as a function of each plasma biomarker separately, and next in a combined model with independent and interactive effects of biomarkers associated with WMH from the individual models.ResultIn individual models, higher WMH volumes were associated with lower plasma Aβ42 (β = ‐0.17, p = 0.032, model R2 = 19.4%) and higher NfL concentrations (β = 0.21, p = 0.013, model R2 = 20.3%). Plasma P‐tau181 (β = ‐0.015, p = 0.851) and GFAP (β = 0.05, p = 0.593) were not significantly associated with WMH volume. Aβ42 and NfL did not demonstrate an interaction but both remained independently associated with WMH volume (Aβ42: β = ‐0.19, p = 0.015; NfL: β = 0.24, p = 0.005; model R2 = 22.7%). No significant interactions between other biomarkers were found.ConclusionPlasma Aβ42 and NfL concentrations associate with burden of cSVD as quantified by WMH load on MRI in non‐demented older adults. As a non‐specific marker of axonal injury, plasma NfL may have utility in studies of brain degeneration related to cSVD. Future studies are warranted to identify factors that may be mediating the effect of plasma amyloid on WMH.

Disentangling the heterogeneity of brain atrophy in Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia. In AD patients, structural MRI analyses have identified various brain atrophy patterns, which are likely the result of differences in regional pathology distribution and variable presence of co‐pathologies.MethodWe included 496 ADNI participants and applied our robust collaborative clustering approach (RCC) to the MRI scans of the Aβ+ participants. RCC removes noise while simultaneously clustering subjects and features. Group comparisons were performed applying Kruskal‐Wallis analyses for quantitative variables and chi‐square tests for categorical variables (Table 1). Power transformations were used to normalize the distribution of quantitative variable for linear regression analyses. APOE ε4 presence and white matter hyperintensity (WMH) volume were included as predictors. P‐values &lt;0.05 were considered statistically significant.ResultWe identified three distinct atrophy clusters among the Aβ+ participants (Table 1). A “limbic predominant” atrophy cluster showed greater cingulate and right hippocampus, inferior and middle temporal lobe atrophy than the cognitively unremarkable (CU) Aβ‐ reference group (Figure 1). The diffuse atrophy cluster showed greater parieto‐occipital‐temporal atrophy. The “hippocampus sparing” atrophy cluster showed a similar neocortical atrophy pattern except for less atrophy in the temporal lobe. The limbic predominant cluster participants had a higher APOE ε4 prevalence than the hippocampal sparing cluster participants (Table 1, 2). The three clusters had higher baseline ADAS‐Cog13 and flortaucipir SUVR binding in all the Braak staging‐defined areas than the CU Aβ‐ reference group (Table 3). The diffuse atrophy cluster had higher ADAS‐Cog13 scores, florbetapir composite scores, and flortaucipir SUVRs in all the Braak staging‐defined areas than the two other atrophy clusters. The hippocampal sparing atrophy cluster participants were older and had higher WMH volumes than the limbic predominant atrophy cluster and the CU Aβ‐ reference group participants.ConclusionOur clustering method discovered three reproducible atrophy patterns in AD, including typical and atypical presentations. This finding likely reflects different combinations of co‐pathology leading to the development of AD, some of which are captured with MRI. Mainly, WMH contributed to the heterogeneity of AD and the atypical neocortical variant.

Higher systolic and diastolic blood pressures in recently postmenopausal women are associated with higher white matter hyperintensity volume more than a decade later in the keeps continuation study

AbstractBackgroundWomen have higher rates of hypertension at the time of menopausal transition than men. Although elevated systolic and diastolic blood pressures (SBP and DBP) are risk factors for white matter (WM) injury both in women and men, WM hyperintensities (WMH), a marker of WM injury, are more common in women than in men after the age of 60. Thus, women may be vulnerable to the effects of elevated BP on WM integrity during menopausal transition. We investigated the association of BP in recently postmenopausal women with good cardiovascular health with WMH volume assessed 13 years later.MethodWomen (n = 212; median age = 67; range 58‐72), who were previously enrolled in a multi‐site randomized menopausal hormone therapy trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59). Participants who were on antihypertensive medications at KEEPS baseline were excluded from the analysis (n = 34). Approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions, WM integrity was assessed with automated WMH volume measurements from 3D‐FLAIR MRI. Associations of baseline SBP and DBP with logWMH volume measured 13 years later were tested by linear regression analyses. Model 1 was adjusted for age, study site, and total intracranial volume. Model 2 was adjusted for covariates of model 1, triglycerides, low density lipoproteins, and waist/hip ratio.ResultThe median SBP was 116 (range 83‐158) and DBP was 74 (range 56‐98). Higher SBP was associated with greater WMH volume (model 1:p = 0.005; model 2:p = 0.005). Similarly, higher DBP was associated with greater WMH volume (model 1:p = 0.008; model 2:p = 0.006) (Figure 1). Neither menopausal hormone therapies versus placebo, nor having high/low SBP (≥120/&lt;120) modified these associations. Voxel‐based analyses demonstrate the association of BPs with the spatial distribution of WMHs (Figure 2).ConclusionHigher BPs in recently menopausal women were associated with greater WM injury more than a decade later after adjusting for CVD risk factors. Early postmenopausal stage is a critical time for BP control in women, which may reduce the risk of WM injury later in life.

Racial and ethnic differences in the relationship between financial worry and white matter hyperintensities in Latinx, non-Latinx Black, and non-Latinx White older adults

Socioeconomic status (SES) is associated with white matter hyperintensities (WMHs) and contributes to racial and ethnic health disparities. However, traditional measures of SES may not accurately represent individual financial circumstances among non-Latinx Black and Latinx older adults due to longstanding structural inequities. This study examined associations between multiple SES indicators (education, income, subjective financial worry) and WMHs across non-Latinx Black, Latinx, and non-Latinx White older adults in the Washington Heights-Inwood Columbia Aging Project (N = 662). Latinx participants reported the lowest SES and greatest financial worry, while Black participants evidenced the most WMHs. Greater financial worry was associated with higher WMHs volume above and beyond education and income, which were not associated with WMHs. However, this association was only evident among Latinx older adults. These results provide evidence for the minority poverty hypothesis and highlight the need for systemic socioeconomic interventions to alleviate brain health disparities in older adulthood.

Blood-brain barrier leakage hotspots collocating with brain lesions due to sporadic and monogenic small vessel disease.

Blood-brain barrier (BBB) is known to be impaired in cerebral small vessel disease (SVD), and is measurable by dynamic-contrast enhancement (DCE)-MRI. In a cohort of 69 patients (42 sporadic, 27 monogenic SVD), who underwent 3T MRI, including DCE and cerebrovascular reactivity (CVR) sequences, we assessed the relationship of BBB-leakage hotspots to SVD lesions (lacunes, white matter hyperintensities (WMH), and microbleeds). We defined as hotspots the regions with permeability surface area product highest decile on DCE-derived maps within the white matter. We assessed factors associated with the presence and number of hotspots corresponding to SVD lesions in multivariable regression models adjusted for age, WMH volume, number of lacunes, and SVD type. We identified hotspots at lacune edges in 29/46 (63%) patients with lacunes, within WMH in 26/60 (43%) and at the WMH edges in 34/60 (57%) patients with WMH, and microbleed edges in 4/11 (36%) patients with microbleeds. In adjusted analysis, lower WMH-CVR was associated with presence and number of hotspots at lacune edges, and higher WMH volume with hotspots within WMH and at WMH edges, independently of the SVD type. In conclusion, SVD lesions frequently collocate with high BBB-leakage in patients with sporadic and monogenic forms of SVD.

Association of Blood Lipid Profile Components with White Matter Hyperintensity Burden in Cerebral Small Vessel Disease.

Cerebral small vessel disease (CSVD) refers to a common cerebrovascular disease and white matter hyperintensities (WMHs) constitute a typical feature of CSVD. However, there has not been a large number of studies investigating the relationship between lipid profile components and WMHs. Altogether, 1019 patients with CSVD were enrolled at the First Affiliated Hospital of Zhengzhou University between April 2016 to December 2021. Baseline data were collected for all patients, including demographic characteristics and clinical data. WMH volumes were evaluated by two experienced neurologists using the MRIcro software. Multivariate regression analysis was used to investigate the relationship among the severity of WMHs, blood lipids and common risk factors. Altogether, 1019 patients with CSVD were enrolled, including 255 in the severe WMH group and 764 in the mild WMH group. After including age, sex and blood lipids to construct a multivariate logistic regression equation, we observed that the severity of WMHs was independently predicted by low-density lipoprotein (LDL), homocysteine level and history of cerebral infarction. We used WMH volume, a highly accurate measure, to assess its relationship with lipid profiles. The WMH volume increased with a decrease in LDL. This relationship was more significant, especially among the subgroups of patients aged <70 years and men. Patients with cerebral infarction and higher homocysteine levels were more likely to have higher WMH volumes. Our study has provided a reference for clinical diagnosis and therapy, especially for discussing the role of blood lipid profiles in the pathophysiology of CSVD.

Gait and falls in cerebral small vessel disease: a systematic review and meta-analysis.

Gait impairment contributes to falls and frailty. Some studies suggest that cerebral small vessel disease (CSVD) is associated with gait impairment in the general population. We systematically reviewed and meta-analysed the literature on associations of CSVD with gait impairment and falls. The protocol was published in PROSPERO (CRD42021246009). Searches of Medline, Cochrane and Embase databases were conducted on 30 March 2022. Cross-sectional and longitudinal studies of community-dwelling adults were included, reporting relationships between diagnosis or neuroimaging markers of CSVD and outcomes related to gait or falls. Partial correlation coefficients were calculated and pooled using a random-effects model for meta-analysis. The search retrieved 73 studies (53 cross-sectional; 20 longitudinal). Most studies reported an association between CSVD and gait impairments or falls risk: 7/7 studies on CSVD score or diagnosis, 53/67 studies on white matter hyperintensities (WMHs), 11/21 studies on lacunar infarcts, 6/15 studies on cerebral microbleeds and 1/5 studies on perivascular spaces. Meta-analysis of 13 studies found that higher WMH volume was mildly correlated with lower gait speed, in all studies (r = -0.23, 95% confidence interval: -0.33 to -0.14, P < 0.0001). However, there was significant heterogeneity between studies (I2 = 82.95%; tau2 = 0.02; Q = 79.37, P < 0.0001), which was unexplained by variation in age, sex, study quality or if the study adjusted for age. Findings suggest that CSVD severity is associated with gait impairment, history of falls and risk of future falls. Prevention of CSVD should be part of a comprehensive public health strategy to improve mobility and reduce risk of falls in later life.

Abstract 130: History Of Pregnancy Induced Hypertension Is Associated With Markers Of Cerebral Small Vessel Disease: The Northern Manhattan Study And Washington Heights-Hamilton Heights-Inwood Columbia Aging Project

Background: A history of pregnancy-induced hypertension (PIH) is associated with higher risk of developing cerebrovascular disease. Data are lacking on the relationship between PIH, chronic hypertension, and MRI markers of cerebral small vessel disease (CSVD) in older people. Methods: We recruited parous individuals without dementia from the Northern Manhattan Study and the Washington Heights-Inwood Washington Heights-Hamilton Heights-Inwood Columbia Aging Project, two long-running prospective cohort studies in New York City. Detailed obstetric and medical histories were obtained by interview. We defined history of PIH as self-report of at least one pregnancy complicated by gestational hypertension, preeclampsia or eclampsia. We categorized participants as having no hypertension, current hypertension without history of PIH, or current hypertension with history of PIH. Number and location of infarcts and white matter hyperintensity (WMH) volume was assessed by MRI. We used generalized linear models to compare imaging outcomes between groups, adjusting for demographics and cardiovascular risk factors. To account for the effects of early onset hypertension, we performed a sensitivity analysis in NOMAS participants only, adjusting for hypertension as a time varying covariate. Results: A total of 221 participants were interviewed (mean age 69 years [SD 7.5]; 22% white, 28% non-Hispanic Black, 48% Hispanic) of whom 128 (58%) had current hypertension without history of PIH, and 16 (7%) had current hypertension with history of PIH. Adjusting for covariates, hypertensive participants with a history of PIH had higher WMH volume, but no difference in deep silent brain infarcts (Table). Conclusions: In a multiethnic cohort of older parous individuals, those with hypertension and a history of PIH had the highest volume of WMH, suggesting a higher burden of CSVD.

Amyloid-PET of the white matter: Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aβ-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aβ-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aβ-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in Aβ-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aβ-PET related more closely to higher cortical Aβ (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aβ-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.

Twenty-four hour blood pressure variability and the prevalence and the progression of cerebral white matter hyperintensities

Blood pressure variability (BPV) is related to cerebral white matter hyperintensities (WMH), but longitudinal studies assessing WMH progression are scarce. Patients with cardiovascular disease and control participants of the Heart-Brain Connection Study underwent 24-hour ambulatory blood pressure monitoring and repeated brain MRI at baseline and after 2 years. Using linear regression, we determined whether different measures of BPV (standard deviation, coefficient of variation, average real variability (ARV), variability independent of the mean) and nocturnal dipping were associated with WMH and whether this association was mediated or moderated by baseline cerebral perfusion. Among 177 participants (mean age: 65.9 ± 8.1 years, 33.9% female), the absence of diastolic nocturnal dipping was associated with higher WMH volume at baseline (β = 0.208, 95%CI: 0.025–0.392), but not with WMH progression among 91 participants with follow-up imaging. None of the BPV measures were associated with baseline WMH. Only 24-hour diastolic ARV was significantly associated with WMH progression (β = 0.144, 95%CI: 0.030–0.258), most profound in participants with low cerebral perfusion at baseline (p-interaction = 0.042). In conclusion, absent diastolic nocturnal dipping and 24-hour diastolic ARV were associated with higher WMH volume. Whilst requiring replication, these findings suggest that blood pressure patterns and variability may be a target for prevention of small vessel disease.

The associations of energy adjusted dietary inflammatory index with brain structure and cognitive function

&lt;p&gt;Limited research exists on the mediating effect of brain structure in the association between dietary inflammatory index (DII) and cognitive impairment. To address this issue, this analysis utilized data from a cohort of 15,526 participants in the UK Biobank who underwent brain magnetic resonance imaging (MRI) during 2014-2020. We assessed the associations between energy adjusted DII (E-DII, calculated by 28 components) and cognitive function (represented by fluid intelligence scores, FIS), as well as the brain structures, including total brain volume (TBV), white matter volume (WMV), white matter hyperintensities volume (WMHV) and grey matter volume (GMV) of 76 cortices, 14 subcortices and 28 cerebellum regions. We further estimated the mediation effects of brain structures on the association between E-DII and cognitive function. From this analysis, we observed that higher E-DII was associated with reduced TBV, GMV, WMV, FIS and higher WMHV. Each one unit increase in E-DII was associated with 0.025(0.007, 0.041) FIS decrease, 937.93 mm&lt;sup&gt;3&lt;/sup&gt; (95% CI: 494.48.07, 1,381.38) GMV decrease, 675.02 mm&lt;sup&gt;3&lt;/sup&gt; (95% CI: 279.02, 1,071.02) WMV decrease and 93.80 mm&lt;sup&gt;3&lt;/sup&gt; (95% CI: 41.45, 146.14) WMHV increase. Furthermore, GMV, WMHV, WMV were found to significantly mediate the association between E-DII and cognitive function, accounting for 21.82% (95% CI: 11.26%, 33.24%), 19.19% (95% CI: 8.52%, 30.63%) and 4% (95% CI: 1.31%, 7.99%). These results indicated that controlling of inflammatory diet could prevent brain structures abnormalities and might reduce the risk of cognitive impairment.&lt;/p&gt;

White matter hyperintensity, neurofilament light chain, and cognitive decline.

We aimed to determine whether combining white matter hyperintensity (WMH) with neurofilament light chain (NfL) could provide additional information for cognition in older adults. Utilizing data from the population-based Chicago Health and Aging Project, we studied 701 individuals with both biomarkers and cognitive data during the follow-up period. NfL was measured using an ultrasensitive immunoassay, single-molecule array technology. MRI scans of the brain were acquired using 1.5-T systems. Global cognitive function was created as a composite measure of four neuropsychological tests, standardized and averaged to z-scores. Multivariable linear mixed-effects models were used to evaluate the association of WMH and NfL with the rate of cognitive decline. Higher WMH and NfL were associated with a faster rate of cognitive decline during the follow-up; -coefficients (95%CIs) were -0.011 (-0.02, -0.001) and -0.010 (-0.017, -0.003), respectively. In individuals with lower concentration of NfL (i.e., bottom tertile), a higher WMH volume was associated with a faster cognitive decline ( : -0.030; 95%CI -0.046, -0.014). Similarly, in individuals with lower volumes of WMH (i.e., bottom tertile), a higher concentrations of NfL was associated with a faster cognitive decline ( : -0.023; 95%CI -0.042, -0.005). When we combined WMH with NfL, we noted a graded association with increasing volumes of WMH, particularly in people with lower NfL values. While both biomarkers, WMH and NfL, were similarly associated with the annual rate of cognitive decline, our study suggests that they provide different underlying mechanisms affecting cognition.

Hormonal factors moderate the associations between vascular risk factors and white matter hyperintensities.

To examine the moderation effects of hormonal factors on the associations between vascular risk factors and white matter hyperintensities in men and women, separately.White matter hyperintensities were automatically segmented and quantified in the UK Biobank dataset (N = 18,294). Generalised linear models were applied to examine (1) the main effects of vascular and hormonal factors on white matter hyperintensities, and (2) the moderation effects of hormonal factors on the relationship between vascular risk factors and white matter hyperintensities volumes.In men with testosterone levels one standard deviation higher than the mean value, smoking was associated with 27.8% higher white matter hyperintensities volumes in the whole brain. In women with a shorter post-menopause duration (one standard deviation below the mean), diabetes and higher pulse wave velocity were associated with 28.8% and 2.0% more deep white matter hyperintensities, respectively.These findings highlighted the importance of considering hormonal risk factors in the prevention and management of white matter hyperintensities.

Distinct dimensions of depression are associated with different brain‐related biomarkers

AbstractBackgroundManagement of depression, a potentially modifiable risk factor for dementia, is of great importance in older adults with Type 2 Diabetes (T2D), specifically because of their higher risk for both conditions. We previously showed in older adults (aged ≥65) with T2D in the Israel Diabetes and Cognitive Decline (IDCD) study, that different depression‐dimensions were associated with distinct patterns of cognitive outcomes. Specifically, apathy, but not other depression‐dimensions, was associated with faster decline in executive functions. Here, we investigated the cross‐sectional relationship between depression‐ dimensions with different neuropathologies, i.e., total gray matter (GM) volume, white matter hyper‐intensities (WMH) and amyloid burden.MethodAmong IDCD participants [mean age = 70.55 (SD = 4.25), 38.5% female], 209 had a brain MRI, 42 of whom also had an amyloid PET. Depression dimensions were defined based on the Geriatric Depression Scale‐ 15 item (GDS‐ 15): dysphoric mood, apathy, anxiety, hopelessness and subjective memory complaint. Gray Matter and WMH volumes were examined using a high‐resolution 3‐Tesla brain MRI. Amyloid‐β burden was defined as mean standardized uptake value ratios (SUVRs) of [18F] flutemetamol in the frontal, parietal, and temporal cortices compared to the cerebellum as reference region. We used two‐step linear regression models to study the association of GDS–domains and brain imaging markers.ResultHigher total GDS score was associated with lower GM volume (r = ‐0.14; p = 0.037) and higher volume of WMH (r = 0.20; p = 0.003), but not with brain amyloid‐β burden (r = ‐0.13; p = 0.37). Among specific depression‐ dimensions, apathy (r = 0.22; p = 0.001), and hopelessness (r = 0.15; p = 0.033) were associated with higher WMH burden, whereas the subjective memory complaints dimension was associated with lower total GM volume (r = ‐0.15; p = 0.026). Depression dimensions were not associated with amyloid burden.ConclusionIn cognitively normal older adults with T2D, higher depression scores, even below the cutoff defined as clinically significant, were associated with lower GM and higher WMH volumes. Apathy was the main driver of the association with higher WMH burden and subjective memory complaints drove the association with brain atrophy. No association was found between depression‐dimensions and amyloid‐β burden, consistent with previous findings in non‐T2D samples, on the role of vascular, rather than AD pathology, in depression.

Association of Liver Fibrosis with Cognitive Test Performance and Brain Volume Changes in the UK Biobank Study

AbstractBackgroundLiver fibrosis is a chronic liver condition that, though frequently subclinical, has widespread systemic effects. We hypothesized that liver fibrosis is associated with worse cognitive performance and corresponding brain imaging changes.MethodWe examined the association of liver fibrosis with cognition and brain volumes among adults in the UK Biobank study, which prospectively enrolled approximately 500,000 people starting in 2007 and subsequently collected cognitive test and brain MRI data for some participants. We included participants with available liver fibrosis, cognitive test, and brain imaging data. Liver fibrosis was defined at baseline using validated cutoffs of the Fibrosis‐4 (FIB‐4) liver fibrosis score. The primary cognitive test outcome was the Digit Symbol Substitution Test (DSST), a multidomain test. Secondary cognitive test outcomes were executive function tests (Trails A, Trails B, Reaction Time) and memory tests (Numeric Memory, Pairs Matching). The primary imaging outcome was white matter hyperintensity volume; secondary outcomes were hippocampal volume and total brain volume. We used multiple linear regression models to evaluate the association of liver fibrosis with cognitive test performance and brain volumes while adjusting for potential confounders.ResultsAmong 105,313 participants with cognitive test data, the mean age was 56.1 years and 56% were women. Standard liver chemistries were largely in the normal range. However, 2.0% (95% CI, 1.9‐2.1%) had liver fibrosis based on FIB‐4 scores. Cognitive tests were completed a median of 5.8 years after baseline liver fibrosis assessment. After adjusting for demographics, socioeconomics, education, body mass index, metabolic syndrome, hypertension, diabetes, dyslipidemia, and tobacco and alcohol use, liver fibrosis was associated with worse performance on the DSST (β = ‐0.40; 95% CI, ‐0.60, ‐0.20; P&lt;0.001) (Figure). Liver fibrosis was associated with worse executive function but not memory test performance (Table). We included 34,730 participants with brain MRI, obtained a median of 9.3 years after baseline. In adjusted models, liver fibrosis was associated with lower hippocampal volume (β = ‐58.8; 95% CI, ‐94.7, ‐22.9; P = 0.001) and higher white matter hyperintensity volumes (β = 1142.8; 95% CI, 311.6, 1973.9; P = 0.007) (Table, Figure).ConclusionLiver fibrosis is associated with worse cognitive performance, perhaps explained by hippocampal volume loss and white matter hyperintensity burden.

Cardiac function and neuropathological substrates on MRI across age span: A Cross‐Cohort Collaboration (CCC)

AbstractBackgroundCardiac dysfunction has been linked to an increased risk of dementia. However, the underlying pathophysiological substrates remain largely unspecified due to considerable heterogeneity in prior studies. We aggregated data from seven community‐based studies within the Cross‐Cohort Collaboration, to study the association between cardiac function and brain health.MethodsParticipants from all cohorts underwent echocardiography to assess systolic function (left ventricular ejection fraction (LVEF)) and diastolic function (EA‐ratio, deceleration time (DT)). High‐resolution brain MRI was performed to compute volumes of total brain (TBV), gray matter, white matter, hippocampus, and white matter hyperintensities (WMH). We used multivariable linear regression models to determine the association of echocardiographic measures and clinical heart failure with brain volumes, pooling the results using random‐effects meta‐analysis.ResultsAmong 10,307 individuals (median age: 62.5 years [54.7 – 70.5]; 54.9% women), moderate to severe systolic function was associated with lower total brain volume (beta per 1‐SD decrease: ‐0.18; 95%CI [‐0.32 ‐ ‐0.04], I2=36%), most profound for white matter and hippocampal volumes. Impaired relaxation in the diastolic phase was associated with smaller total brain volumes (‐0.10; 95%CI [‐0.16 ‐ ‐0.04], I2=2%), again driven by white matter and the hippocampi. Restrictive diastolic function similarly predisposed to lower hippocampal volume (‐0.16; 95%CI [‐0.31 ‐ ‐0.01], I2=0%). Diastolic dysfunction, but not systolic function, was associated with higher volume of WMH (0.03; 95%CI [0.01‐0.05]; I2=0% for DT). Of 8055 participants with clinical data, 277 (3.4%) had heart failure, which was related to all lower brain volumes. These results were consistent across cohorts. In stratified analyses, higher LVEF was associated with higher TBV, from age 50‐59 years onwards up until the oldest age category (80+ years), including larger hippocampi (0.04; 95%CI [0.00‐0.08]; I2=0%) for those aged between 50‐59 years.ConclusionCardiac dysfunction is associated with brain imaging markers of neurodegeneration in community‐dwelling individuals from midlife to late‐life. Preservation of cardiac function may be an additional target to promote cognitively healthy ageing.

Predicting Cognitive Decline in Older Adults Using Baseline Metrics of AD Pathologies, Cerebrovascular Disease, and Neurodegeneration.

Dementia is a growing socioeconomic challenge that requires early intervention. Identifying biomarkers that reliably predict clinical progression early in the disease process would better aid selection of individuals for future trial participation. Here, we compared the ability of baseline, single time-point biomarkers (CSF amyloid 1-42, CSF ptau-181, white matter hyperintensities (WMH), cerebral microbleeds, whole-brain volume, and hippocampal volume) to predict decline in cognitively normal individuals who later converted to mild cognitive impairment (MCI) (CNtoMCI) and those with MCI who later converted to an Alzheimer disease (AD) diagnosis (MCItoAD). Standardized baseline biomarker data from AD Neuroimaging Initiative 2 (ADNI2)/GO and longitudinal diagnostic data (including ADNI3) were used. Cox regression models assessed biomarkers in relation to time to change in clinical diagnosis using all follow-up time points available. Models were fit for biomarkers univariately and together in a multivariable model. Hazard ratios (HRs) were compared to evaluate biomarkers. Analyses were performed separately in CNtoMCI and MCItoAD groups. For CNtoMCI (n = 189), there was strong evidence that higher WMH volume (individual model: HR 1.79, p = 0.002; fully adjusted model: HR 1.98, p = 0.003) and lower hippocampal volume (individual: HR 0.54, p = 0.001; fully adjusted: HR 0.40, p < 0.001) were associated with conversion to MCI individually and independently. For MCItoAD (n = 345), lower hippocampal (individual model: HR 0.45, p < 0.001; fully adjusted model: HR 0.55, p < 0.001) and whole-brain volume (individual: HR 0.31, p < 0.001; fully adjusted: HR 0.48, p = 0.02), increased CSF ptau (individual: HR 1.88, p < 0.001; fully adjusted: HR 1.61, p < 0.001), and lower CSF amyloid (individual: HR 0.37, p < 0.001; fully adjusted: HR 0.62, p = 0.008) were most strongly associated with conversion to AD individually and independently. Lower hippocampal volume was a consistent predictor of clinical conversion to MCI and AD. CSF and brain volume biomarkers were predictive of conversion to AD from MCI, whereas WMH were predictive of conversion to MCI from cognitively normal. The predictive ability of WMH in the CNtoMCI group may be interpreted as some being on a different pathologic pathway, such as vascular cognitive impairment.

Increased regional white matter hyperintensity volume in objectively-defined subtle cognitive decline and mild cognitive impairment

White matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase risk of developing mild cognitive impairment (MCI) and Alzheimer's disease (AD). Less is known about the extent and pattern of WMH in pre-MCI stages, such as among those with objectively-defined subtle cognitive decline (Obj-SCD). Five hundred and fifty-nine Alzheimer's Disease Neuroimaging Initiative participants (170 cognitively unimpaired [CU]; 83 Obj-SCD; 306 MCI) free of clinical dementia or stroke completed neuropsychological testing and MRI exams. ANCOVA models compared cognitive groups on regional WMH adjusting for age, sex, and apolipoprotein E (APOE) ɛ4 frequency. Compared with the CU group, those with Obj-SCD had greater temporal, occipital, and frontal WMH whereas those with MCI had higher WMH volume across all regions (p’s < 0.01). No differences in WMH volume were observed between the Obj-SCD and MCI groups (p’s > 0.05). Findings add to growing evidence of associations between Obj-SCD and imaging biomarkers, providing support for utility of these criteria to capture subtle cognitive changes that are biologically based.

Association of Subjective Memory Complaints With White Matter Hyperintensities and Cognitive Decline Among Older Adults in Chicago, Illinois

ImportanceSubjective memory complaints (SMCs) are associated with a faster cognitive decline; whether this association is also associated with structural brain alterations, such as white matter hyperintensity (WMH) volumes, requires investigation.ObjectiveTo evaluate the association of SMCs with WMH volumes and cognitive decline and investigate the role of WMH volumes in the association between SMCs and cognitive decline.Design, Setting, and ParticipantsThe Chicago Health and Aging Project, a population-based cohort study, enrolled adults aged 65 years or older. Data collection occurred in 3-year cycles from 1993 until 2012. Our study comprised 975 participants with magnetic resonance imaging assessments, of which 900 participants had data on SMCs and covariates, and 713 participants provided 2 or more cognitive assessments during the follow-up. Statistical analyses were conducted from May to October 2021.ExposuresSMCs were obtained from self-reported questionnaire data during clinical evaluations, and the cycle, when reported, constituted the baseline of our study. Based on the frequency and severity of concerns, we categorized participants into 3 groups, (1) no concerns, (2) moderate concerns, and (3) very worried.Main Outcomes and MeasuresVolumetric magnetic resonance imaging measures of WMH volume and neuropsychological testing assessments of global cognition. Linear regression analysis was used to investigate the association between SMCs and WMH volumes in a multivariable model adjusted for age, sex, race and ethnicity, education, APOE4 status, and total intracranial volume. The association of SMCs with cognitive decline was investigated using linear mixed-effects models for age, sex, race and ethnicity, education, APOE4 status, follow-up time, and each variable in interaction with time to estimate the annual longitudinal change in cognitive function.ResultsOf the 900 participants with data on SMCs, covariates, and WMH volumes, 553 (61.4%) were women, 539 (59.9%) were African American, and the mean (SD) age was 79.5 (6.2) years. SMCs were associated with a larger WMH volume and faster cognitive decline. Compared with participants with no concerns, participants who were very worried had higher WMH volumes (β = 0.833; 95% CI, 0.203-1.463) and 174% faster cognitive decline (β = −0.049; 95% CI, −0.076 to −0.022). The association between SMCs and cognitive decline remained statistically significant among individuals with large WMH volumes (ie, within the fourth quartile). Within the fourth quartile of WMH volumes, participants who were very worried had 428% faster cognitive decline (β = −0.077; 95% CI, −0.144 to −0.011) compared with participants with no concerns.Conclusions and RelevanceThis cohort study suggests that SMCs, frequently reported by older individuals, are an important sign of cognitive impairment, especially among people with abnormalities in brain structure, such as larger WMH volumes.