Greater White Matter Hyperintensities Burden Research Articles

Sex-Specific Risk Factors and Clinical Dementia Outcomes for White Matter Hyperintensities in a large South Korean Cohort.

White matter hyperintensities (WMH) on brain MRI images are the most common feature of cerebral small vessel disease (CSVD). Studies have yielded divergent findings on the modifiable risk factors for WMH and WMH's impact on cognitive decline. Mounting evidence suggests sex differences in WMH burden and subsequent effects on cognition. Thus, we aimed to identify sex-specific modifiable risk factors for WMH. We then explored whether there were sex-specific associations of WMH to longitudinal clinical dementia outcomes. Participants aged 49-89 years were recruited at memory clinics and underwent a T2-weighted fluid-attenuated inversion recovery (FLAIR) 3T MRI scan to measure WMH volume. Participants were then recruited for two additional follow-up visits, 1-2 years apart, where clinical dementia rating sum of boxes (CDR-SB) scores were measured. We first explored which known modifiable risk factors for WMH were significant when tested for a sex-interaction effect. We additionally tested which risk factors were significant when stratified by sex. We then tested to see whether WMH is longitudinally associated with clinical dementia that is sex-specific. The study utilized data from 713 participants (241 males, 472 females) with a mean age of 72.3 years and 72.8 years for males and females, respectively. 57.3% and 59.5% of participants were diagnosed with mild cognitive impairment (MCI) for males and females, respectively. 40.7% and 39.4% were diagnosed with dementia for males and females, respectively. Of the 713 participants, 181 participants had CDR-SB scores available for three longitudinal time points. Compared to males, females showed stronger association of age to WMH volume. Type 2 Diabetes was associated with greater WMH burden in females but not males. Finally, baseline WMH burden was associated with worse clinical dementia outcomes longitudinally in females but not in males. Elderly females have an accelerated increase in cerebrovascular burden as they age, and subsequently are more vulnerable to clinical dementia decline due to CSVD. Additionally, females are more susceptible to the cerebrovascular consequences of diabetes. These findings emphasize the importance of considering sex when examining the consequences of CSVD. Future research should explore the underlying mechanisms driving these sex differences and personalized prevention and treatment strategies. The BICWALZS is registered in the Korean National Clinical Trial Registry (Clinical Research Information Service; identifier, KCT0003391). Registration Date 2018/12/14.

Relationship between carotid intima-media thickness and white matter hyperintensities in non-stroke adults: a systematic review.

Literature suggests a common pathophysiological ground between carotid atherosclerosis (CAS) and white matter alterations in the brain. However, the association between carotid intima-media thickness (CIMT) and white matter hyperintensities (WMH) has not been conclusively reported. The current systematic review explores and reports the relationship between CIMT and WMH among asymptomatic/non-stroke adults. A recent literature search on PubMed, SCOPUS, and Web of Science databases was conducted in compliance with the PRISMA protocol. The pre-defined Population-Intervention-Comparison-Outcome-Study (PICOS) criteria included observational studies investigating the CIMT-WMH association among non-stroke adults undergoing magnetic resonance imaging and carotid ultrasound. Out of 255 potential results, 32 studies were critically assessed for selection, and finally, 10 articles were included, comprising 5,116 patients (females = 60.2%; males = 39.8%) aged between 36-71 years. The included studies earned high quality ratings (6-9) based on the Newcastle-Ottawa-Scale criteria. Qualitative synthesis showed a significantly parallel relationship between increased CIMT and greater WMH burden in 50% of the studies. In addition, significant risk factors related to the CIMT-WMH association included older age, hypertension, depression, migraine, Hispanic ethnicity, and apolipoprotein E (ɛ4) in postmenopausal women. Overall, the cumulative evidence showed a consistent CIMT-WMH association in asymptomatic middle-aged and older non-stroke adults, indicating that CAS may contribute to the progression of pathologically hyperintense white matter in the brain. However, further research is warranted to infer the plausible relationship between CIMT and WMH in the absence of stroke.

White Noise—Is Anxiety in Late-Life Associated With White Matter Hyperintensity Burden?

We investigated the relationship between anxiety phenotypes (global anxiety, worry, and rumination) and white matter hyperintensities (WMH), with special consideration for the roles of age and executive function (EF). Our hypotheses were 1) anxiety phenotypes would be associated with WMH and 2) EF would moderate this relationship. Cross-sectional. Participants were recruited from the local community (Pittsburgh, PA). We recruited 110 older adults (age ≥ 50) with varying worry severity and clinical comorbidity. Not applicable. Demographics (age, sex, race, education), clinical measures (cumulative illness burden, global anxiety, worry, and rumination), EF, and WMH quantified with magnetic resonance imaging. Lower global anxiety and worry severity were significantly correlated with higher WMH volume, though the global anxiety relationship was not significant after controlling for age. Rumination as not associated with WMH burden. EF was not correlated with either global anxiety, worry, rumination, or WMH. However, in those with advanced age and/or greater WMH burden, there was an association between worry and EF as well as EF and WMH. Longitudinal studies are needed in order to clarify the complex interactions between anxiety phenotypes, WMH, and EF.

Mild behavioral impairment is associated with sleep apnea, insomnia and brain white matter hyperintensity burden

AbstractBackgroundMild behavioral impairment (MBI) is a neurobehavioral syndrome associated with increased risk for Alzheimer’s disease (AD) and other neurodegenerative disorders. White matter hyperintensities (WMH) are brain lesions associated with cerebrovascular insult and contribute to cognitive decline across the cognitive spectrum (normal cognition, mild cognitive impairment (MCI) and dementia). Sleep disturbance is common among older adults with cognitive impairment and like MBI, is a modifiable AD risk factor that can affect brain structure including WMH. We sought to examine the prevalence of MBI and its relationship with sleep and WMH in a community cohort of older adults.MethodParticipants enrolled in the Wake Forest AD Research Center (ADRC) Clinical Core cohort (N = 633, mean age = 70.4 years) provided history of sleep apnea and insomnia, underwent neuropsychological assessment and neuropsychiatric symptom assessment, as reported by an informant on the Neuropsychiatric Inventory Questionnaire (NPI‐Q). MBI scores were derived from the NPI‐Q severity and included 10 symptoms reflecting affective dysregulation, impulse control, decreased motivation, social inappropriateness and abnormal perception or thought content, and excluded NPI‐Q questions on sleep and appetite. T1 and T2 FLAIR MRI were obtained; T1 and FLAIR were segmented to quantify WMH volume, which was scaled by head size and log transformed. Global cognitive status was assessed using the clinical dementia rating (CDR) global score.ResultIn our sample, 24% of participants had MBI. Normal cognition (CDR = 0) participants had significantly lower rates of MBI compared to both MCI (CDR = 0.5) and dementia (CDR ≥ 1, Figure 1, p<.001). MBI scores were also significantly higher in participants with than without sleep apnea (Fig. 2, p = 0.003) and insomnia (Figure 3, p = 0.043). Further, WMH volume was higher in participants with MBI (Figure 4, p<.001).ConclusionMBI increased in prevalence with cognitive impairment. Sleep disturbances and greater WMH burden in our MBI participants may increase their risk of cognitive decline for normal cognition and MCI groups and relate to poor behavioral and health outcomes in participants with dementia. Future studies will assess interactions of sleep, MBI and WMH across cognitive groups and their association with risk of conversion to MCI or AD.

Hypoattenuated leaflet thickening is associated with silent brain injury

Abstract Background The association between hypoattenuated leaflet thickening (HALT) following transcatheter aortic valve implantation (TAVI) and stroke remains contradictory. Whether HALT carries an increased risk of subclinical brain injury (SBI) has not been investigated. Purpose We investigated whether HALT is associated with SBI on MRI. Furthermore, we assessed whether post-TAVR SBI impacts the patients' cognition and outcome. Methods 153 patients undergoing TAVR were prospectively enrolled. Brain MRI was performed shortly post-TAVR and 6 months (6M) later to assess the occurrence of acute silent cerebral ischaemic lesions (SCIL) and chronic white matter hyperintensities (WMH). HALT was screened by cardiac CT angiography 6M post-TAVR. Neurocognitive evaluation was performed before, shortly after and 6M following TAVR. Results At 6M, 115 patients had diagnostic CTA and 10 had HALT. HALT status, baseline and follow-up MRIs were available in 91 cases. At 6M, new SCIL was evident in 16%, new WMH in 66%. New WMH was more frequent (100% vs 62%; p=0.047) with higher median volume (319 vs 50 mm3; p=0.039) among HALT-patients. In uni- and multivariate analysis, HALT was associated with new WMH volume (beta: 0.72; 95% CI: 0.2–1.39; p=0.009). The patients' cognitive trajectory from pre-TAVR to 6M showed significant association with the 6M SCIL volume (beta: −4.69; 95% CI: −9.13 to −027; p=0.038), but was not related to the presence or volume of new WMH. During a 3.1-year follow-up neither HALT, nor the related WMH burden was related with increased mortality (HALT HR: 0.86, 95% CI: 0,202–3,687; p=0.84; new WMH HR: 1.09; 95% CI: 0,701–1,680; p=0.71). Conclusions 6M post-TAVR, HALT was linked with greater WMH burden, but did not carry an increased risk of cognitive decline or mortality over a 3.1-year follow-up. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): János Bolyai Scholarship of the Hungarian Academy of Sciences

Subclinical leaflet thrombosis after transcatheter aortic valve implantation is associated with silent brain injury on brain magnetic resonance imaging.

Whether hypoattenuated leaflet thickening (HALT) following transcatheter aortic valve implantation (TAVI) carries a risk of subclinical brain injury (SBI) is unknown. We investigated whether HALT is associated with SBI detected on magnetic resonance imaging (MRI), and whether post-TAVI SBI impacts the patients' cognition and outcome. We prospectively enrolled 153 patients (age: 78.1 ± 6.3 years; female 44%) who underwent TAVI. Brain MRI was performed shortly post-TAVI and 6 months later to assess the occurrence of acute silent cerebral ischaemic lesions (SCIL) and chronic white matter hyperintensities (WMH). HALT was screened by cardiac computed tomography (CT) angiography (CTA) 6 months post-TAVI. Neurocognitive evaluation was performed before, shortly after and 6 months following TAVI. At 6 months, 115 patients had diagnostic CTA and 10 had HALT. HALT status, baseline, and follow-up MRIs were available in 91 cases. At 6 months, new SCIL was evident in 16%, new WMH in 66%. New WMH was more frequent (100 vs. 62%; P = 0.047) with higher median volume (319 vs. 50 mm3; P = 0.039) among HALT-patients. In uni- and multivariate analysis, HALT was associated with new WMH volume (beta: 0.72; 95%CI: 0.2-1.39; P = 0.009). The patients' cognitive trajectory from pre-TAVI to 6 months showed significant association with the 6-month SCIL volume (beta: -4.69; 95%CI: -9.13 to 0.27; P = 0.038), but was not related to the presence or volume of new WMH. During a 3.1-year follow-up, neither HALT [hazard ratio (HR): 0.86; 95%CI: 0.202-3.687; P = 0.84], nor the related WMH burden (HR: 1.09; 95%CI: 0.701-1.680; P = 0.71) was related with increased mortality. At 6 months post-TAVI, HALT was linked with greater WMH burden, but did not carry an increased risk of cognitive decline or mortality over a 3.1-year follow-up (NCT02826200).

Brain Changes and Fast Cognitive and Motor Decline in Older Adults.

To identify brain magnetic resonance imaging (MRI) signatures characterizing people with different patterns of decline in cognition and motor function. In the Swedish National Study on Aging and Care in Kungsholmen, Stockholm, 385 participants had available repeated brain MRI examinations, where markers of brain volumes and white matter integrity were assessed. The speed of cognitive and motor decline was estimated as the rate of a Mini-Mental State Examination and gait speed decline over 12 years (linear mixed models), and further dichotomized into the upper (25% fastest rate of decline) versus the lower quartiles. Participants were grouped in slow/no decliners (reference), isolated motor decliners, isolated cognitive decliners, and cognitive and motor decliners. We estimated the associations between changes in brain markers (linear mixed models) and baseline diffusion tensor imaging measures (linear regression model) and the 4 decline patterns. Individuals with concurrent cognitive and motor decline (n = 51) experienced the greatest loss in the total brain (β: -12.3; 95% confidence interval [CI]: -18.2; -6.38) and hippocampal (β: -0.25; 95% CI: -0.34; -0.16) volumes, the steepest accumulation of white matter hyperintensities (β: 1.61; 95% CI: 0.54; 2.68), and the greatest ventricular enlargement (β: 2.07; 95% CI: 0.67; 3.47). Compared to the reference, those only experiencing cognitive decline presented with steeper hippocampal volume loss, whereas those exhibiting only motor decline displayed a greater white matter hyperintensities burden. Lower microstructural white matter integrity was associated with concurrent cognitive and motor decline. Concurrent cognitive and motor decline is accompanied by rapidly evolving and complex brain pathology involving both gray and white matter. Isolated cognitive and motor declines seem to exhibit brain damage with different qualitative features.

Sympathoexcitatory Responses to Isometric Handgrip Exercise Are Associated With White Matter Hyperintensities in Middle-Aged and Older Adults.

Vascular dysfunction may occur prior to declines in cognitive function and accumulation of neuropathology. White matter hyperintensities (WMH) develop due to cerebral ischemia and elevated blood pressure in midlife. The purpose of this study was to evaluate associations between cardiovascular and cerebrovascular responses to sympathoexcitatory stimuli and WMH burden in cognitively unimpaired middle-aged and older adults. Sixty-eight adults (age = 63 ± 4y, men = 20, women = 48) participated in this study. Participants completed isometric handgrip exercise (IHG) exercise at 40% of maximal voluntary contraction until fatigue followed by a 90s period of post-exercise ischemia. Heart rate (HR), mean arterial pressure (MAP), middle cerebral artery blood velocity (MCAv), and end-tidal CO2 were continuously measured throughout the protocol. Cerebrovascular resistance index (CVRi) was calculated as MAP/MCAv. WMH lesion volume and intracranial volume (ICV) were measured using a FLAIR and T1 scan on a 3T MRI scanner, respectively. WMH fraction was calculated as (WMH lesion volume/ICV)*100 and cubic root transformed. Multiple linear regressions were used to determine the association between cardiovascular and cerebrovascular responses to IHG exercise and post-exercise ischemia and WMH fraction. Multiple linear regression models were adjusted for age, sex, apolipoprotein ε4 status, and total work performed during IHG exercise. During IHG exercise, there were significant increases from baseline in HR (25 ± 12%), MAP (27 ± 11%), MCAv (5 ± 10%), and CVRi (22 ± 17%; P < 0.001 for all). During post-exercise ischemia, HR (8 ± 7%), MAP (22 ± 9%), and CVRi (23 ± 16%) remained elevated (P < 0.001) while MCAv (0 ± 10%) was not different compared to baseline. There was an inverse association between the percent change in HR (r = −0.42, P = 0.002), MAP (r = −0.41, P = 0.002), and CVRi (r = −0.31, P = 0.045), but not MCAv (r = 0.19, P = 0.971) in response to IHG exercise and WMH fraction. There were no associations between responses to post-exercise ischemia and WMH fraction. Lower sympathoexcitatory responses to IHG exercise are associated with greater WMH burden in middle-aged to older adults. These findings suggest that individuals who demonstrate smaller increases in HR, MAP, and CVRi in response to sympathoexcitatory stress have greater WMH burden.

Middle‐Aged and Older Adults with Greater White Matter Hyperintensity Burden Display Attenuated Blood Pressure and Cerebral Blood Velocity Responses During Orthostatic Tilt

Cerebral autoregulation (CA) is the process by which the brain maintains adequate blood flow despite sudden changes to perfusion pressure. White matter hyperintensities (WMH) are associated with increased risk of cerebrovascular disease and dementia. This study investigated whether dynamic CA is reduced in cognitively unimpaired middle‐aged and older adults. Additionally, we evaluated dynamic CA and cerebrovascular responses at rest and in response to orthostatic tilt. We hypothesized that CA would be impaired during orthostatic tilt and that diminished blood pressure and cerebral artery blood velocity changes would be associated with greater WMH fraction. We studied 33 middle‐aged and older adults (age = 63 ± 4 y). Intracranial volume (ICV) and WMH lesion volume were measured using a T1 and FLAIR scan, respectively, on a 3T MRI scanner. WMH fraction was calculated as the cube root of (WMH lesion volume/ICV) *100. CA was measured using middle cerebral artery blood velocity (MCAv) from transcranial Doppler ultrasound and beat‐to‐beat mean arterial pressure (MAP) from a finger cuff. Five minutes of data were collected at rest and during 60º orthostatic tilt. Transfer function analysis was used to quantify dynamic CA and reported as gain and phase at low frequency (LF) (0.07‐0.20 Hz). MCAv, MAP and cerebrovascular resistance index (CVRi; calculated as MAP/MCAv) were used to quantify the cerebrovascular response to orthostatic tilt. LF gain was greater at baseline compared to 60º tilt (0.52 cm/s/mmHg vs 0.46 cm/s/mmHg, p &lt; 0.05); however, there were no differences in LF phase between baseline and 60º tilt (29.70 degrees vs 29.42 degrees, p = 0.95). During 60º tilt, MAP and MCAv decreased compared to baseline (MAP: 106 mmHg vs 101 mmHg, p = 0.02; MCAv: 59 cm/s vs 53 cm/s, p &lt; .01). CVRi was higher at 60º tilt compared with baseline (1.90 mmHg/cm/s vs 2.02 mmHg/cm/s, p &lt; 0.01). There were significant inverse associations between the percent change from baseline to 60º tilt in MAP (r = ‐0.4, p = 0.03), MCAv (r = ‐0.39, p = 0.03), but not CVRi (r = 0.13, p = 0.50), and WMH fraction. There were no associations at baseline or 60º tilt between gain (Baseline: r = ‐0.18, p = 0.33; 60º: r = ‐0.31, p = 0.09) or phase (Baseline: r = 0.07, p = 0.71; 60º: r = ‐0.29, p = 0.12) and WMH fraction. Our results indicate that dynamic CA is preserved in cognitively unimpaired adults during tilt. However, individuals with diminished MAP and MCAv responses to orthostatic tilt displayed greater WMH fraction. Future studies are needed to investigate the relationship between blood pressure and cerebral blood flow in individuals with cognitive impairment to further understand the role of cerebral blood flow regulation in the development of cognitive decline.

Oxygen Metabolic Stress and White Matter Injury in Patients With Cerebral Small Vessel Disease.

Chronic hypoxia-ischemia is a putative mechanism underlying the development of white matter hyperintensities (WMH) and microstructural disruption in cerebral small vessel disease. WMH fall primarily within deep white matter (WM) watershed regions. We hypothesized that elevated oxygen extraction fraction (OEF), a signature of hypoxia-ischemia, would be detected in the watershed where WMH density is highest. We further hypothesized that OEF would be elevated in regions immediately surrounding WMH, at the leading edge of growth. In this cross-sectional study conducted from 2016 to 2019 at an academic medical center in St Louis, MO, participants (age >50) with a range of cerebrovascular risk factors underwent brain magnetic resonance imaging using pseudocontinuous arterial spin labeling, asymmetric spin echo, fluid-attenuated inversion recovery and diffusion tensor imaging to measure cerebral blood flow (CBF), OEF, WMH, and WM integrity, respectively. We defined the physiologic watershed as a region where CBF was below the 10th percentile of mean WM CBF in a young healthy cohort. We conducted linear regression to evaluate the relationship between CBF and OEF with structural and microstructural WM injury defined by fluid-attenuated inversion recovery WMH and diffusion tensor imaging, respectively. We conducted ANOVA to determine if OEF was increased in proximity to WMH lesions. In a cohort of 42 participants (age 50-80), the physiologic watershed region spatially overlapped with regions of highest WMH lesion density. As CBF decreased and OEF increased, WMH density increased. Elevated watershed OEF was associated with greater WMH burden and microstructural disruption, after adjusting for vascular risk factors. In contrast, WM and watershed CBF were not associated with WMH burden or microstructural disruption. Moreover, OEF progressively increased while CBF decreased, in concentric contours approaching WMH lesions. Chronic hypoxia-ischemia in the watershed region may contribute to cerebral small vessel disease pathogenesis and development of WMH. Watershed OEF may hold promise as an imaging biomarker to identify individuals at risk for cerebral small vessel disease progression.

CSF p‐Tau/Aβ40 ratio predicts longitudinal hypometabolism and cognitive decline in amyloid‐negative elderly adults

AbstractBackgroundTauopathy can be measured with PET imaging and CSF phosphorylated tau (p‐Tau), and recent studies have suggested that CSF p‐Tau may be superior to tau PET for detecting early tau increase. We recently found the use of a CSF p‐Tau/Aβ40 ratio improved the associations with Alzheimer’s disease (AD) biomarkers over CSF p‐Tau. However, the significance of elevated CSF p‐Tau in the absence of abnormal Aβ is unclear, as is how it relates to neurodegeneration, cognitive decline, and other factors.MethodWe analyzed 201 non‐demented ADNI participants who were Aβ‐ on both CSF Aβ42/Aβ40 and PET, and who had concurrent Aβ PET, CSF (Aβ40, Aβ42 and p‐Tau181), white matter hyperintensities (WMH), and vascular risk factors measured within one year. Of these, 81 individuals had 18F‐fluorodeoxyglucose (FDG) PET and adjusted hippocampal volume (aHCV). We also examined available longitudinal CSF, aHCV, FDG PET and Preclinical Alzheimer’s Cognitive Composite (PACC) measurements in 20‐40% of participants.ResultIn Aβ‐ individuals, older age, male sex, greater WMH burden and hypertension (Fig. 1) were related to elevated CSF p‐Tau/Aβ40, which was associated with temporoparietal (metaROI) hypometabolism and hippocampal atrophy (Fig. 2). Longitudinally, lower CSF Aβ42/Aβ40, higher WMH, and hypertension predicted faster CSF p‐Tau/Aβ40 increase over around 5 years (Fig. 1), and higher CSF p‐Tau/Aβ40 predicted faster FDG SUVR decrease (Fig. 2) over around 3 years. Furthermore, baseline CSF p‐Tau/Aβ40 was associated with subsequent PACC decline over around 5 years, and this was partially mediated by glucose metabolism and fully mediated by hippocampal atrophy (Fig. 3).ConclusionOur results suggest that both cerebrovascular disease and subthreshold levels of Aβ, as well as age, are related to CSF p‐Tau/Aβ40 accumulation. Crucially, evidence of this CSF tau pathology shares features with AD including an AD‐like pattern of hypometabolism and hippocampal atrophy. Thus, this phenotype of Aβ‐ CSF tau elevation is similar to AD, which implies that it may represent an Aβ‐independent pathway to AD, a clinical syndrome that mimics AD, or very early interaction between Aβ and vascular disease that underlies neurodegeneration and cognitive decline.

High precision plasma Aβ42/Aβ40 ratio detects early amyloid deposition in non‐demented elderly adults

AbstractBackgroundPlasma Aβ42/Aβ40 ratio measured by an immunoprecipitation and liquid chromatography–mass spectrometry assay showed high accordance with amyloid PET. However, it is still unclear about the risk factors related to plasma Aβ42/Aβ40, whether it can detect Aβ pathology earlier than Aβ PET, and how it relates to tau deposition, neurodegeneration and cognitive decline. In this study, we aim to investigate: 1) the risk factors related to plasma Aβ42/Aβ40; 2) the concordance and discordance of plasma Aβ42/Aβ40 and Aβ PET, and their associations with tau deposition at follow‐up and perspective changes of Aβ PET, neurodegeneration and cognition in cognitively unimpaired (CU) and mild cognitive impairment (MCI) elderly adults.MethodWe analyzed 181 (97 CU, 85 MCI) ADNI participants with plasma Aβ42/Aβ40, Aβ PET, white matter hyperintensities (WMH), vascular factors, adjusted hippocampal volume (aHCV) measured by structural MRI, 18F‐fluorodeoxyglucose (FDG) PET and memory score obtained within one year. The associations of plasma Aβ42/Aβ40 with age, sex, APOE‐ε4 status, vascular risk factors were tested using Pearson’s correlation or Mann‐Whitney U test. Participants were classified into Plasma±/PET± groups according to the thresholds of plasma Aβ42/Aβ40 and Aβ PET (Fig.2A). Longitudinal changes of Aβ accumulation, aHCV, FDG PET and cognition, and tau PET measured at a mean of 5.32±1.24 years later were compared among different Plasma±/PET± groups.ResultWe found older age, APOE‐ε4 carrier and greater WMH burden (Fig.1) were significantly related to reduced plasma Aβ42/Aβ40. Plasma Aβ42/Aβ40 may become abnormal earlier than Aβ PET. Plasma+/PET‐ individuals were accumulating Aβ burden in early‐affected brain regions (Fig. 2), had no evidence of tau deposition, neurodegeneration and cognitive decline at follow‐up (Fig. 3), suggesting Plasma+/PET‐ individuals are very likely in the very early stage of Alzheimer’s disease (AD).ConclusionIn summary, our results suggest that age, APOE4 carrier and white matter lesion may be related to lower plasma Aβ42/Aβ40. Individuals with abnormal plasma Aβ42/Aβ40 but normal Aβ PET may be at early stage of Aβ pathology, are significantly accumulating Aβ in AD typical cortical regions. These findings may provide useful reference for screening Aβ+ participants by using plasma Aβ42/Aβ40.

Cardiac Hypertrophy Is Associated With Advanced Brain Aging in the General Population.

BackgroundHypertrophy of the left ventricle (LV) has recently been associated with adverse changes of brain structure in older adults, notably increased burden of white matter hyperintensities (WMHs). Whether greater LV size or mass is also related to WMH burden in middle‐aged adults is currently unclear. In addition, its relation with alterations in cortical thickness (CT) has not been studied to date.Methods and ResultsData from 1602 participants of the population‐based SHIP (Study of Health in Pomerania) with LV ejection fraction >40% and no history of myocardial infarction were included (aged 21–82 years; median age, 49 years; 53% women). Participants underwent both echocardiography and magnetic resonance imaging of the head. Imaging markers of brain aging (ie, CT and WMH volume) were determined from magnetic resonance imaging scans. LV mass and diameter were associated with lower global CT and greater WMH volume, while adjusting for age, sex, body height, fat‐free body mass, and intracranial volume. Moreover, thicknesses of the interventricular septum and posterior wall were also associated with lower global CT. These associations could not be explained by cardiovascular risk factors (including hypertension), inflammatory markers, or sociodemographic factors. Regional analyses showed distinct spatial patterns of lower CT in association with LV diameter and posterior wall thickness.ConclusionsLV diameter and mass are associated with lower global and regional CT as well as greater WMH burden in the general population. These findings highlight the brain structural underpinnings of the associations of LV hypertrophy with cognitive decline and dementia.

White matter hyperintensities and risk of levodopa-induced dyskinesia in Parkinson's disease.

ObjectiveTo investigate whether the burden of white matter hyperintensities (WMHs) is associated with the risk of developing levodopa‐induced dyskinesia (LID) in Parkinson’s disease (PD).MethodsAccording to the Clinical Research Center for Dementia of South Korea WMH visual rating scale, 336 patients with drug‐naïve early stage PD (follow‐up >3 years) were divided into two groups of PD with minimal WMHs (PD‐WMH–; n = 227) and moderate‐to‐severe WMHs (PD‐WMH+; n = 109). The Cox regression model was used to estimate the hazard ratio for the development of LID in the PD‐WMH + group compared with the PD‐WMH– group, while adjusting for age at PD onset, sex, striatal dopamine depletion, and PD medication dose. Additionally, we assessed the effects of WMH burden rated by the Scheltens scale and regional WMH distribution on the development of LID.ResultsPatients in the PD‐WMH + group were older and had more severe parkinsonian motor signs despite comparable striatal dopamine transporter availability than those in the PD‐WMH– group. Patients in the PD‐WMH + group had a higher risk of developing LID (hazard ratio, 2.66; P < 0.001) than those in the PD‐WMH– group after adjustment for other confounding factors. A greater WMH burden was associated with earlier occurrence of LID (hazard ratio, 1.04; P = 0.001), although the effects of WMHs on LID development did not exhibit region‐specific patterns.InterpretationThe present study demonstrates that the burden of WMHs is associated with occurrence of LID in patients with PD, suggesting comorbid WMHs as a risk factor for LID.

Frailty and Its Correlates in Adults With Late Life Depression

To investigate the rates of frailty and frailty characteristics and examine the clinical and neuropsychological correlates of frailty in adults with late life depression (LLD). Data were used from the evaluation of 134 individuals over the age of 60 years (45 men, 89 women) with a depressive diagnosis who enrolled in studies for the treatment of their depression. Depression, neuropsychological functioning, white matter hyperintensity (WMH) burden via magnetic resonance imaging, and characteristics of frailty were assessed. Fried frailty burden (≥3 characteristics) was present in 25% of the sample, with this rate increasing to 45.5% when using clinically meaningful cut-scores for gait speed (<1 m/s) and physical activity levels (<1000 kcal/week). Moreover, 62% of the sample exhibited gait slowing (<1 m/s) or weakness (grip strength), with 29% demonstrating both. Greater frailty burden was associated with greater Hamilton Depression Rating Scale severity in covariate adjusted linear regression models (t127 = 2.41, p = 0.02). Greater frailty burden was not associated with neuropsychological dysfunction, nor was it associated with greater WMH burden. Findings from this study show that frailty, specifically physical frailty deficits in mobility and strength, is highly comorbid in adults with LLD, associated with greater depressive symptom severity, and does not appear to be associated with the vascular depression subtype of LLD. Future research should investigate the relationship between frailty and antidepressant treatment response as well as test whether there are age-related biological processes that result in the manifestation of the frail-depressed subtype of LLD.

APOE ε4, white matter hyperintensities, and cognition in Alzheimer and Lewy body dementia.

ObjectiveTo determine if APOE ε4 influences the association between white matter hyperintensities (WMH) and cognitive impairment in Alzheimer disease (AD) and dementia with Lewy bodies (DLB).MethodsA total of 289 patients (AD = 239; DLB = 50) underwent volumetric MRI, neuropsychological testing, and APOE ε4 genotyping. Total WMH volumes were quantified. Neuropsychological test scores were included in a confirmatory factor analysis to identify cognitive domains encompassing attention/executive functions, learning/memory, and language, and factor scores for each domain were calculated per participant. After testing interactions between WMH and APOE ε4 in the full sample, we tested associations of WMH with factor scores using linear regression models in APOE ε4 carriers (n = 167) and noncarriers (n = 122). We hypothesized that greater WMH volume would relate to worse cognition more strongly in APOE ε4 carriers. Findings were replicated in 198 patients with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI-I), and estimates from both samples were meta-analyzed.ResultsA significant interaction was observed between WMH and APOE ε4 for language, but not for memory or executive functions. Separate analyses in APOE ε4 carriers and noncarriers showed that greater WMH volume was associated with worse attention/executive functions, learning/memory, and language in APOE ε4 carriers only. In ADNI-I, greater WMH burden was associated with worse attention/executive functions and language in APOE ε4 carriers only. No significant associations were observed in noncarriers. Meta-analyses showed that greater WMH volume was associated with worse performance on all cognitive domains in APOE ε4 carriers only.ConclusionAPOE ε4 may influence the association between WMH and cognitive performance in AD and DLB.

Association of Blood Pressure Variability and Intima-Media Thickness With White Matter Hyperintensities in Hypertensive Patients

Background and Purpose: Ambulatory blood pressure variability (ABPV), ABP, and carotid intima-media thickness (IMT) are closely associated with white matter hyperintensities (WMH), and few studies focused on establishing effective models based on ABP, ABPV, and IMT to predict the WMH burden. We aimed to evaluate the value of a predictive model based on the metrics of ABP, ABPV, and IMT, which were independently associated with the WMH burden.Methods: We retrospectively enrolled 140 hypertensive inpatients for physical examinations in Shanghai East Hospital, Tongji University School of Medicine between February 2018 and January 2019. The basic clinical information of all subjects was recorded, and we also collected the metrics of ABP, ABPV, and IMT. Patients with Fazekas scale grade ≥2 were classified into heavy burden of WMH group. Then, we analyzed the association between all characteristics and the WMH burden. Multivariate analysis was performed to assess whether the metrics of ABP, ABPV, and IMT were independently associated with WMH, and we used receiver operating characteristic (ROC) to evaluate the value of predictive model based on the metrics of ABP, ABPV, and IMT.Results: Higher WMH grade was associated with increasing age, diabetes mellitus, higher total cholesterol (TC), higher low-density lipoprotein (LDL), higher IMT, higher 24-h systolic blood pressure (SBP), higher daytime SBP, higher nocturnal SBP, 24-h and daytime standard deviation (SD) of SBP, and 24-h SBP weight SD; 24-h SBP, 24-h SBP-SD, and IMT were independently related to the burden of WMH even after adjusting for the clinical variables. In addition, we also established a model that has a higher predictive capacity using 24-h SBP, 24-h SBP-SD, and IMT in the ROC analysis to assess the WMH burden in hypertensive patients.Conclusions: Higher 24-h SBP, higher 24-h SBP-SD, and larger IMT were independently associated with a greater burden of WMH among elderly primary hypertension Asian patients. Establishing a model based on these factors might provide a new approach for enhancing the accuracy of diagnosis of WMH using metrics in 24-h ABPM and carotid ultrasound.

Central Arterial Stiffness Is Associated With Structural Brain Damage and Poorer Cognitive Performance: The ARIC Study.

BackgroundCentral arterial stiffening and increased pulsatility, with consequent cerebral hypoperfusion, may result in structural brain damage and cognitive impairment.Methods and ResultsWe analyzed a cross‐sectional sample of ARIC‐NCS (Atherosclerosis Risk in Communities–Neurocognitive Study) participants (aged 67–90 years, 60% women) with measures of cognition (n=3703) and brain magnetic resonance imaging (n=1255). Central arterial hemodynamics were assessed as carotid‐femoral pulse wave velocity and pressure pulsatility (central pulse pressure). We derived factor scores for cognitive domains. Brain magnetic resonance imaging using 3‐Tesla scanners quantified lacunar infarcts; cerebral microbleeds; and volumes of white matter hyperintensities, total brain, and the Alzheimer disease signature region. We used logistic regression, adjusted for demographics, apolipoprotein E ɛ4, heart rate, mean arterial pressure, and select cardiovascular risk factors, to estimate the odds of lacunar infarcts or cerebral microbleeds. Linear regression, additionally adjusted for intracranial volume, estimated the difference in log‐transformed volumes of white matter hyperintensities, total brain, and the Alzheimer disease signature region. We estimated the mean difference in cognitive factor scores across quartiles of carotid‐femoral pulse wave velocity or central pulse pressure using linear regression. Compared with participants in the lowest carotid‐femoral pulse wave velocity quartile, participants in the highest quartile of carotid‐femoral pulse wave velocity had a greater burden of white matter hyperintensities (P=0.007 for trend), smaller total brain volumes (−18.30 cm3; 95% CI, −27.54 to −9.07 cm3), and smaller Alzheimer disease signature region volumes (−1.48 cm3; 95% CI, −2.27 to −0.68 cm3). These participants also had lower scores in executive function/processing speed (β=−0.04 z score; 95% CI, −0.07 to −0.01 z score) and general cognition (β=−0.09 z score; 95% CI, −0.15 to −0.03 z score). Similar results were observed for central pulse pressure.ConclusionsCentral arterial hemodynamics were associated with structural brain damage and poorer cognitive performance among older adults.

Relationship between carotid arterial properties and cerebral white matter hyperintensities.

Since arterial stiffness is a functional measure of arterial compliance and may be an important marker of cerebrovascular disease, we examined the association of carotid artery stiffness with white matter hyperintensity volume (WMHV) in a cross-sectional study of 1,166 stroke-free participants. Carotid beta stiffness index (STIFF) was assessed by M-mode ultrasound of the common carotid artery and calculated as the ratio of natural log of the difference between systolic and diastolic blood pressure over STRAIN, a ratio of the difference between carotid systolic and diastolic diameter (DD) divided by DD. WMHV was measured by fluid-attenuated inversion recovery MRI. The associations of STIFF, DD, and STRAIN with WMHV were examined using linear regression after adjusting for sociodemographic, lifestyle, and vascular risk factors. In a fully adjusted model, larger carotid DD was significantly associated with greater log-WMHV (β = 0.09, p = 0.001). STIFF and STRAIN were not significantly associated with WMHV. In adjusted analyses stratified by race-ethnicity, STRAIN (β = -1.78, p = 0.002) and DD (β = 0.11, p = 0.001) were both associated with greater log-WMHV among Hispanic participants, but not among black or white participants. Large carotid artery diameters are associated with greater burden of white matter hyperintensity (WMH) in this multiethnic population. The association between increased diameters, decreased STRAIN, and greater WMH burden is more pronounced among Hispanics. These associations suggest a potential important pathophysiologic role of extracranial large artery remodeling in the burden of WMH.

Association of Kidney Function Biomarkers with Brain MRI Findings: The BRINK Study.

Chronic kidney disease (CKD) studies have reported variable prevalence of brain pathologies, in part due to low inclusion of participants with moderate to severe CKD. To measure the association between kidney function biomarkers and brain MRI findings in CKD. In the BRINK (BRain IN Kidney Disease) study, MRI was used to measure gray matter volumes, cerebrovascular pathologies (white matter hyperintensity (WMH), infarctions, microhemorrhages), and microstructural changes using diffusion tensor imaging (DTI). We performed regression analyses with estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR) as primary predictors, and joint models that included both predictors, adjusted for vascular risk factors. We obtained 240 baseline MRI scans (150 CKD with eGFR <45 in ml/min/1.73 m2; 16 mild CKD: eGFR 45-59; 74 controls: eGFR≥60). Lower eGFR was associated with greater WMH burden, increased odds of cortical infarctions, and worsening diffusion changes throughout the brain. In eGFR models adjusted for UACR, only cortical infarction associations persisted. However, after adjusting for eGFR, higher UACR provided additional information related to temporal lobe atrophy, increased WMH, and whole brain microstructural changes as measured by increased DTI mean diffusivity. Biomarkers of kidney disease (eGFR and UACR) were associated with MRI brain changes, even after accounting for vascular risk factors. UACR adds unique additional information to eGFR regarding brain structural and diffusion biomarkers. There was agreater impact of kidney function biomarkers on cerebrovascular pathologies and microstructural brain changes, suggesting that cerebrovascular etiology may be the primary driver of cognitive impairment in CKD.