White Matter Hyperintensities Research Articles

MRI-Based Prediction of Macrovascular Causes of Intracerebral Hemorrhage: The MACRO Score.

Although most spontaneous intracerebral hemorrhages (ICHs) are due to cerebral small vessel diseases (SVDs), between 1 in 7 and 1 in 10 are due to a macrovascular cause. Rapid diagnosis has important therapeutic and prognostic implications but sometimes requires digital subtraction angiography (DSA), an invasive procedure which cannot be performed in all patients. MRI provides optimal sensitivity for markers of SVD but was not included in previous risk stratification scores. We aimed to create and validate a risk stratification score for macrovascular causes of ICH including MRI findings to guide diagnosis and further investigations. We pooled data from 2 large observational study cohorts (London/United Kingdom and Graz/Austria) of consecutive patients with ICH who had brain MRI and at least 1 angiographic modality within 90 days of symptom onset. The primary outcome was a macrovascular cause of ICH (arteriovenous malformation/dural arteriovenous fistula, aneurysm, cavernoma, or cerebral venous thrombosis), with the diagnosis based on neurovascular multidisciplinary meetings. Using lasso logistic regression, we built the MRI Assessment of the Causes of intRacerebral haemOrrhage (MACRO) score to assess the probability of a macrovascular cause. We performed internal validation using bootstrapping and external validation in an independent cohort (Bern/Switzerland). We included 1,043 patients with ICH (mean age 66 years, 42% female), 78 of whom had a macrovascular cause (7.5%). The final score includes age (0-39, 40-69, or ≥70), location of ICH (lobar, deep, or infratentorial), and SVD markers on MRI (≥1 microbleed, ≥1 lacune, presence of cortical superficial siderosis, or white matter hyperintensities using the Fazekas scale). The MACRO score showed an optimism-adjusted c-statistic of 0.90 (95% CI 0.88-0.93), superior to existing CT-based scores (p < 0.001). In external validation, the c-statistic was 0.87 (95% CI 0.80-0.94). MACRO scores ≥6 (59.5% of patients) indicated a very low risk of a macrovascular cause (0.2%), while scores ≤2 (9% of patients) indicated a high risk (48.9%). The MRI-based MACRO score shows excellent performance in predicting the likelihood of macrovascular causes of spontaneous intracerebral hemorrhage, making it useful in guiding further investigations. Important limitations include the observational study design and the performance of DSA in a minority of patients.

Higher Long-Term Visit-to-Visit Blood Pressure Variability Is Associated With Severe Cerebral Small Vessel Disease in the General Population.

Long-term visit-to-visit blood pressure (BP) variability is linked to various diseases, but its impact on cerebral small vessel disease (cSVD) burden, and its features remains uncertain. We analyzed 1284 participants from the Kailuan cohort (2006-2022). Visit-to-visit systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) variability were categorized into tertiles (low, middle, high). Magnetic resonance imaging identified white matter hyperintensities (WMH), lacunae of presumed vascular origin (LA), cerebral microbleeds (CMBs), and visible perivascular spaces (PVS). Total cSVD burden was classified as none (0), mild (1), moderate (2), or severe (3-4) based on the presence of these features. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). High SBP variability was associated with moderate cSVD burden (OR = 1.89, 95% CI: 1.09-3.29) and PVS (OR = 1.62, 95% CI: 1.10-2.39). High DBP variability was associated with LA (OR = 1.74, 95% CI: 1.06-2.84). High PP variability showed a significant risk for severe cSVD burden (OR = 2.49, 95% CI: 1.34-4.63). These associations were modified by age and hypertension status. Among young adults (age < 60 years), high PP variability was associated with severe cSVD burden (OR = 3.33, 95% CI: 1.31-8.44), LA (OR = 3.02, 95% CI: 1.31-6.93), and PVS (OR = 1.86, 95% CI: 1.20-2.88). The risk effects of SBP and PP variability on cSVD burden were significant only in participants with hypertension. High long-term visit-to-visit BP variability (BPV), particularly in combination with hypertension, is a significant risk factor for total cSVD. Special attention should be given to PP variability in younger adults.

Two-Stage Recruitment Design to Reduce Magnetic Resonance Imaging Screening Cost for a Theoretical Clinical Trial of White Matter Hyperintensity Progression.

White matter hyperintensities (WMH) and their progression are associated with risk of dementia and stroke, so are an important target for clinical trials. The cost of broad magnetic resonance imaging (MRI) screening to identify eligible individuals, however, limits the feasibility of designing clinical trials targeting WMH. A low-cost retinal or clinical screening measure before MRI could reduce recruitment costs versus an MRI-only screening design in a hypothetical clinical trial. Data from the Atherosclerosis Risk in Communities study with valid retinal and WMH measurements (N=1311) were used. To identify a population at greater likelihood of significant WMH on MRI and thus reduce the number of screening MRIs required, we evaluated 3 theoretical prescreening measures: (1) retinal, (2) clinical, (3) combined clinical-retinal. Given a target sample for clinical trials (N=646), we calculated screening sample sizes based on the proportion within the population having an elevated score for each prescreening measure (separately) multiplied by the proportion of significant WMH among those with that prescreening feature. Recruitment costs were calculated using estimated retinal and MRI cost estimates. Compared with the estimated cost of MRI-only screening (>$4.24 million, requiring MRI on 6526 participants), prescreening for a high clinical score resulted in total cost of $2.47 million, with an initial screening group of 52 778 participants, with MRI in 3801. A high clinical-retinal score cutoff resulted in costs of $2.9 million while requiring 13 572 participants, with 3801 completing MRI. A 2-stage design with low-cost prescreening measures is a promising approach, resulting in reduced theoretical recruitment costs compared with an MRI-only design.

WMH Contributions to Cognitive Impairment: Rationale and Design of the Diverse VCID Study.

As awareness of dementia increases, more individuals with minor cognitive complaints are requesting clinical assessment. Neuroimaging studies frequently identify incidental white matter hyperintensities, raising patient concerns about their brain health and future risk for dementia. Moreover, current US demographics indicate that ≈50% of these individuals will be from diverse backgrounds by 2060. Racial and ethnic minority populations bear a disproportionate burden of vascular risk factors magnifying dementia risk. Despite established associations between white matter hyperintensities and cognitive impairment, including dementia, no study has comprehensively and prospectively examined the impact of individual and combined magnetic resonance imaging measures of white matter injury, their risk factors, and comorbidities on cognitive performance among a diverse, nondemented, stroke-free population with cognitive complaints over an extended period of observation. The Diverse VCID (Diverse Vascular Cognitive Impairment and Dementia) study is designed to fill this knowledge gap through 3 assessments of clinical, behavioral, and risk factors; neurocognitive and magnetic resonance imaging measures; fluid biomarkers of Alzheimer disease, vascular inflammation, angiogenesis, and endothelial dysfunction; and measures of genetic risk collected prospectively over a minimum of 3 years in a cohort of 2250 individuals evenly distributed among Americans of Black/African, Latino/Hispanic, and non-Hispanic White backgrounds. The goal of this study is to investigate the basic mechanisms of small vessel cerebrovascular injury, emphasizing clinically relevant assessment tools and developing a risk score that will accurately identify at-risk individuals for possible treatment or clinical therapeutic trials, particularly individuals of diverse backgrounds where vascular risk factors and disease are more prevalent.

Predictive effect of nonarteritic anterior ischemic optic neuropathy on the development of cerebral small vessel disease: a retrospective study

ObjectiveThe study aims to determine the correlation between cerebral small vessel diseases (SVDs) and nonarteritic anterior ischemic optic neuropathy (NAION). Additionally, investigate whether NAION raises the risk of an increased total cerebral small vessel disease score (CSVD score) compared to control group without ocular conditions.Methods101 controls without any retinal illness and 61 individuals with NAION were enrolled for this retrospective case control study. Ophthalmic examinations and brain magnetic resonance imaging (MRI) scans were performed on all participants. Data on demographics and clinical characteristics were obtained from hospital medical records. We evaluated and compared the distribution of SVDs and rated the total CSVD score based on SVD indications observed on MRI scans.ResultsSVDs were more frequently in NAION individuals than in control group (82%, p &amp;lt; 0.001), and their odds ratio was 4.11 (95%CI: 1.93–8.79, p &amp;lt; 0.001). The ordinal logistic regression showed patients in NAION group had 3.08-, 5.66- and 2.90-times higher risk than in control group, at each point of the white matter hyperintensity (WMH) score (95%CI: 1.43–6.79, p = 0.003), perivascular spaces (PVS) score (95%CI: 2.31–14.9, p &amp;lt; 0.001) and CSVD score (95%CI: 1.32–6.51, p = 0.005) respectively. Dyslipidemia presented a higher risk in the presence of SVDs (p = 0.008, OR = 2.31, 95%CI: 1.20–4.44) and WHM score (p = 0.018, OR = 2.22, 95%CI: 1.07–4.70). There was no significant difference between NAION group and controls in sex, age, or other past medical characteristics.ConclusionThe predictive effect of NAION on SVDs is possible as NAION patients have an increased risk with SVDs. Brain MRI scans and the control of risk factors associated with SVDs should be recommended for individuals who develop NAION.

Assessment of Immunological, Skeletal, and Thyroid Function Abnormalities in Paediatric Morphoea

Abstract Background: Morphoea is a sclerosing disorder of skin and subcutaneous tissue. Paediatric morphoea shows increased prevalence of various auto-immune diseases, bone deformities, and systemic abnormalities. There is paucity of studies on various immunological, skeletal, and thyroid function abnormalities in paediatric morphoea. Aims and Objectives: To describe immunological, skeletal, and thyroid function abnormalities present in paediatric morphoea patients. Materials and Methods: This cross-sectional study was conducted from January 2021 to March 2023 in the Dermatology outpatient department in a tertiary care hospital. All paediatric morphoea patients were included in this study. All were subjected to detailed history, clinical examination, and investigations including complete blood count, serum IgE, anti-nuclear antibody, thyroid function tests, anti-thyroid peroxidase antibodies, and radiological investigations. Results: A total of 42 children were recruited, out of which 61.90% were females and 38.09% were males. The majority were in the age group of 4–8 years. The most common type of morphoea was encoup de sabre. Anaemia was present in 14.28% patients. Serum IgE levels were raised in 33.33% patients. Thyroid stimulating hormone was raised in 11.9% patients. 33.33% had raised anti-thyroid peroxidase levels. Anti-nuclear antibody titres and rheumatoid factor were raised in 7.14% and 4.76% patients, respectively. Magnetic resonance imaging brain revealed abnormalities in three patients as hyper-intensities in subcortical white matter. Conclusion: Morphoea in children can be associated with varied immunological, osteoarticular, and neurological abnormalities. This study highlights the multi-system involvement in morphoea and the need for larger data and well-designed therapeutic trials for generating evidence-based treatment of this potentially disfiguring disease.

Cerebral microbleeds linked to structural network disruption and cognitive impairment in white matter hyperintensities.

This study aims to explore the relationship between the cerebral microbleeds (CMBs) and white matter structural network in patients with white matter hyperintensities (WMHs), and the correlation with the cognitive impairment. One hundred and fifty-eight participants with WMHs underwent 3.0 T magnetic resonance imaging scans and neuropsychological assessment. The grouping method included count grading with categories: non-CMBs (n-CMBs), CMBs < 5, and CMBs ≥ 5. Additionally, the distribution of CMBs was considered, distinguishing between strictly lobar CMBs (SL-CMBs) and deep or infratentorial CMBs (DI-CMBs). Diffusion tensor imaging was employed to construct the white matter structural network for each participant. Subsequently, we analyzed the correlations between the topological parameters of network and cognitive performance in individuals with CMBs. Compared with n-CMBs group, both CMBs ≥ 5 and DI-CMBs participants exhibited a significant decreased in global efficiency and increased in characteristic path length. Moreover, in the nodal network metrics, the CMBs ≥ 5 showed the left middle occipital gyrus (MOG.L) of nodal efficiency and nodal shortest path correlated with SCWT-A and MMSE, while in the DI-CMBs groups, the left cuneus (CUN.L) of nodal shortest path correlated with SCWT-A. However, there were no significant neuropsychological correlations observed in the SL-CMBs and CMBs < 5 groups. In this study, patients with a high count (≥5) of CMBs or DI-CMBs are associated with disruptions in the microstructure of the white matter structural network, partially impacting the visual network of occipital lobe and affecting the cognitive function of information processing speed and attention.

Sex-Specific Vulnerabilities to Subclinical Vascular Brain Injury in Early Late-Life: The Framingham Heart Study.

Subclinical vascular brain injury is an increasingly recognized risk factor for stroke and dementia. Despite well-established sex differences in vascular risk and disease prevalence, the impact of sex on drivers of subclinical vascular brain injury remains unclear, presenting a barrier to developing sex-specific prevention guidelines. We aimed to establish the extent to which sex moderates associations between vascular risk factors and magnetic resonance imaging (MRI) measures of subclinical brain injury in stroke-free older adults. We leveraged cross-sectional data from 1,579 stroke- and dementia-free Framingham Heart Study Offspring participants at exam 8 (age 65.7 ± 8.8 years, 53% women). Vascular risks were assessed using components of the Framingham Stroke Risk Profile (FSRP) and diastolic blood pressure (DBP). White matter hyperintensity volume (WMH), total cerebral brain volume (TBV), and covert brain infarcts were quantified using MRI. We examined whether vascular risk factors were associated with MRI measures across the combined cohort, and then determined whether sex modified these associations. Higher FSRP and specifically systolic blood pressure (SBP) were associated with greater WMH. These associations were stronger in women and remained after adjusting for menopause age and hormone therapy use. By contrast, diabetes and lower DBP were associated with smaller TBV primarily in men. The DBP-atrophy relationship was only observed in men with declining DBP or prior hypertension. Our findings highlight differential vulnerability to the impact of vascular risk factors on white matter health in women and global atrophy in men, supporting the development of sex-specific guidelines to better preserve vascular brain health in aging. ANN NEUROL 2024.

Cerebrovascular markers of WMH and infarcts in ADNI: A historical perspective and future directions.

White matter hyperintensities (WMH) and infarcts found on magnetic resonance imaging (MR infarcts) are common biomarkers of cerebrovascular disease. In this review, we summarize the methods, publications, and conclusions stemming from the Alzheimer's Disease Neuroimaging Initiative (ADNI) related to these measures. We combine analysis of WMH and MR infarct data from across the three main ADNI cohorts with a review of existing literature discussing new methodologies and scientific findings derived from these data. Although ADNI inclusion criteria were designed to minimize vascular risk factors and disease, data across all the ADNI cohorts found consistent trends of increasing WMH volumes associated with advancing age, female sex, and cognitive impairment. ADNI, initially proposed as a study to investigate biomarkers of AD pathology, has also helped elucidate the impact of asymptomatic cerebrovascular brain injury on cognition within a cohort relatively free of vascular disease. Future ADNI work will emphasize additional vascular biomarkers. HIGHLIGHTS: White matter hyperintensities (WMHs) are common to advancing age and likely reflect brain vascular injury among older individuals. WMH and to a lesser extent, magnetic resonance (MR) infarcts, affect risk for transition to cognitive impairment. WMHs and MR infarcts are present, even among Alzheimer's Disease Neuroimaging Initiative (ADNI) participants highly selected to have Alzheimer's disease (AD) as the primary pathology. WMH burden in ADNI is greater among individuals with cognitive impairment and has been associated with AD neurodegenerative markers and cerebral amyloidosis. The negative additive effects of cerebrovascular disease appear present, even in select populations, and future biomarker work needs to further explore this relationship.

White Matter Hyperintensities and Cognitive Functions in People With the R544C Variant of the NOTCH3 Gene Without Stroke or Dementia.

NOTCH3 pathologic variants cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which presents with stroke and dementia and is characterized by white matter hyperintensities (WMHs) on brain MRI. The R544C variant is a common pathologic variant in Taiwan, but not all carriers exhibit significant symptoms. We investigated whether WMHs occur before clinical symptoms in carriers with pathogenic variants, examined factors associated with WMHs, and explored their relationship with cognitive functions. We enrolled 63 R544C carriers without overt clinical disease (WOCD) and 37 age-matched and sex-matched noncarriers as controls from the Taiwan Precision Medicine Initiative data set. All participants underwent clinical interviews, comprehensive neuropsychological assessments, and brain MRI. We calculated total and regional WMH volumes, determined the age at which WMHs began increasing in carriers, and examined the relationship between WMHs and neuropsychological performance. Factors associated with WMH volumes were analyzed using multivariable linear regression models. Compared with controls, R544C carriers WOCD had increased WMH volume, except in the occipital and midbrain areas, and showed a rapid increase in WMHs starting at age 48. They scored lower on the Mini-Mental State Examination (median = 28.4 vs 29.0, p = 0.048), Montreal Cognitive Assessment (MoCA) (median = 28.3 vs 29.0, p = 0.013), and memory and executive function tests than controls. After adjusting for age, sex, and education, MoCA scores were associated with whole-brain (r = -0.387, padj = 0.008) and regional WMHs (all padj < 0.05) except in the midbrain area. Age (β = 0.034, 95% CI 0.021-0.046, p < 0.001), hypercholesterolemia (β = 0.375, 95% CI 0.097-0.653, p = 0.009), and the vascular risk factor (VRF) index (β = 0.132, 95% CI 0.032-0.242, p = 0.019) were associated with the WMH severity in carriers. Our study revealed that WMHs are extensively distributed in R544C carriers WOCD. They exhibited a rapid increase in WMHs beginning at age 48, approximately 7 years earlier than the reported age at symptomatic onset. Age was the strongest predictive factor of WMHs, and VRF, particularly hypercholesterolemia, might be modifying factors of WMHs.

Associations of Amyloid Burden, White Matter Hyperintensities, and Hippocampal Volume With Cognitive Trajectories in the 90+ Study.

Associations of Amyloid Burden, White Matter Hyperintensities, and Hippocampal Volume With Cognitive Trajectories in the 90+ Study.

Abstract 4126731: Cumulative Cardiovascular Health in Young Adulthood and Systemic Target Organ Damage: The Coronary Artery Risk Development In Young Adults (CARDIA) Study

Introduction: Cardiovascular health (CVH) in young adulthood (YA) is strongly associated with subclinical and clinical outcomes in later life. Longitudinal patterns of CVH exposure through YA (e.g., cumulative CVH exposure) may be particularly important. However, no studies have assessed cumulative CVH in YA and its association with target organ damage (TOD). Methods: CVH was defined using Life’s Essential 8 (LE8) score. CARDIA participants (ppts) with CVH assessed at ≥3 exams over 20 years of follow-up in YA (year [Y]0 to Y20 exams; mean ages 25 to 45 years) were included. Cumulative LE8 scores (cumLE8; higher = better CVH over time) were calculated as the sum of LE8 scores through YA carried forward between exams measured as point*years. Eight markers of TOD (listed in Results) were measured at subsequent exams (Y20 or Y25) including cardiac, renal, pulmonary, and neurologic markers. Associations of cumLE8 with markers of TOD were assessed using partial effects regression models adjusted for race, sex, and maximal education. Results: There were 3,485 ppts (43.4% men, 46.2% Black) with mean cumLE8 score of 1,448.6 (SD 211.4) point*years. Higher cumLE8 in YA was linearly associated with lower measures of cardiac (left ventricular mass index, carotid intima media thickness, prevalence of coronary artery calcium), renal (estimated glomerular filtration rate [eGFR] in men), and neurologic damage (proportion of white matter hyperintensity on brain MRI) ( Figure ). Higher cumLE8 was also linearly associated with better lung function (forced expiratory volume in 1 second, forced vital capacity). Urine albumin-creatinine ratio (in men and women) and eGFR (in women) were non-linearly associated with cumLE8. Conclusions: Our findings underscore the importance of high cumLE8 in YA and its association with reduced onset of TOD later in life. Primordial prevention strategies are needed to achieve and maintain high CVH through the critical period of YA.

Neuropathological Correlates of White Matter Hyperintensities in Cerebral Amyloid Angiopathy.

White matter hyperintensities (WMHs) are frequently observed on magnetic resonance imaging (MRI) in patients with cerebral amyloid angiopathy (CAA). The neuropathological substrates that underlie WMHs in CAA are unclear, and it remains largely unexplored whether the different WMH distribution patterns associated with CAA (posterior confluent and subcortical multispot) reflect alternative pathophysiological mechanisms. We performed a combined invivo MRI-ex vivo MRI-neuropathological study in patients with definite CAA. Formalin-fixed hemispheres from 19 patients with CAA, most of whom also had invivo MRI available, underwent 3T MRI, followed by standard neuropathological examination of the hemispheres and targeted neuropathological assessment of WMH patterns. Exvivo WMH volume was independently associated with CAA severity (P=0.046) but not with arteriolosclerosis (P=0.743). In targeted neuropathological examination, compared with normal-appearing white matter, posterior confluent WMHs were associated with activated microglia (P=0.043) and clasmatodendrosis (P=0.031), a form of astrocytic injury. Trends were found for an association with white matter rarefaction (P=0.074) and arteriolosclerosis (P=0.094). An exploratory descriptive analysis suggested that the histopathological correlates of WMH multispots were similar to those underlying posterior confluent WMHs. This study confirmed that vascular amyloid β severity in the cortex is significantly associated with WMH volume in patients with definite CAA. The histopathological substrates of both posterior confluent and WMH multispots were comparable, suggesting overlapping pathophysiological mechanisms, although these exploratory observations require confirmation in larger studies.

Associations of Circulating Platelet Endothelial Cell Adhesion Molecule-1 Levels With Progression of Cerebral Small-Vessel Disease, Cognitive Decline, and Incident Dementia.

The association between platelet endothelial cell adhesion molecule-1 (PECAM-1) with cerebral small-vessel disease and cognition in dementia-free subjects remains uninvestigated. A prospective cohort of dementia-free subjects was recruited from memory clinics and followed up for 5 years. Annual neurocognitive assessments and twice-yearly brain magnetic resonance imaging scans were performed. Associations of baseline plasma PECAM-1 levels with cerebral small-vessel disease, cognitive decline (Montreal Cognitive Assessment scores and executive function Z scores), and incident dementia were evaluated. Of 213 subjects (aged 70.2±7.7 years, 51.2% men), median PECAM-1 levels were 0.790 (interquartile range, 0.645-0.955 ng/mL). Compared with the highest tertile, subjects within the lowest PECAM-1 tertile had greater cross-sectional white matter hyperintensity volume (β=4.84 [95% CI, 0.67-9.01]; P=0.023), age-related white matter change scores (β=1.39 [95% CI, 0.12-2.67]; P=0.033), and cerebral microbleeds (Adjusted risk ratio, 2.59 [95% CI, 1.19-5.62]; P=0.016). Of the 204 participants with follow-up data (median, 60.0 [interquartile range, 60.0-60.0] months), 24 (11.8%) developed incident dementia. Compared with the highest tertile, subjects within the lower tertiles of PECAM-1 had a higher risk of incident dementia (first tertile: adjusted hazard ratio [AHR], 4.52 [95% CI, 1.35-15.13]; P=0.024; second tertile: AHR, 3.28 [95% CI, 1.02-10.60]; P=0.047). The lowest PECAM-1 tertile was associated with greater progression of white matter hyperintensity volume (β=4.15 [95% CI, 0.06-8.24]; P=0.047), cerebral microbleeds (incident relative risk [IRR], 2.21 [95% CI, 1.05-4.65]; P=0.036), and decline in executive function (β=-0.45 [95% CI, -0.76 to -0.14]; P=0.004), and Montreal Cognitive Assessment (β=-1.32 [95% CI, -2.30 to -0.35]; P=0.008) scores. In dementia-free subjects, lower circulating PECAM-1 levels are associated with greater cerebral small-vessel disease progression and cognitive decline, thus warranting future study as a potential therapeutic target.

Role of Cardiovascular Risk in Associations of Brain-Derived Neurotrophic Factor with Longitudinal Brain and Cognitive Trajectories in Older Adults

ABSTRACT Background Higher levels of brain-derived neurotrophic factor (BDNF) have been associated with better neurocognitive outcomes. BDNF is present in cardiovascular tissue, and some evidence suggests it may benefit cardiovascular function. The current study assessed whether there is a mediating and/or moderating role of cardiovascular health in the relationship between BDNF and brain and cognitive outcomes. Method We examined longitudinal data from 397 older adults (aged 54–89;164 females, 233 males) enrolled in the Alzheimer’s Disease Neuroimaging Initiative with available plasma BDNF, medical, neuroimaging, and cognitive assessments. We used path analysis and linear regression to estimate the mediating and moderating roles of two measures of cardiovascular health, the Framingham Risk Score (FRS) and pulse pressure, in the relationships between BDNF and longitudinal changes in brain structure (white matter hyperintensity volume, hippocampal volume, and primary visual cortex volume) and cognitive function (executive function, episodic memory, and language). Results There was no significant association of plasma BDNF with FRS or pulse pressure (ps > 0.31), precluding mediation. There were no robust associations between BDNF and longitudinal change in any brain structural or cognitive measures (ps > .12). Higher FRS was significantly associated with greater increases in WMH volume (ps < .01). FRS and pulse pressure were not associated with any other brain structural or cognitive outcomes (ps > .07). Conclusion These results suggest that cardiovascular health may not play an important role in the influence of BDNF on neurocognitive health in older adults.

Cortico-limbic volume abnormalities in late life depression are distinct from β amyloid and white matter pathologies.

This study was conducted to clarify patterns of cortico-limbic volume abnormalities in late life depression (LLD) relative to non-depressed (ND) adults matched for amyloid β (Aβ) deposition and to evaluate the relationship of volume abnormalities with cognitive performance. Participants included 116 LLD and 226 ND. Classification accuracy of LLD status was estimated using area under the receiver operator characteristic curve. Twenty-one percent of LLD and ND participants were Aβ positive and the groups did not differ on white matter hyperintensity volume (WMH (logscale); β = 0.12, p = 0.28). Compared to ND, the LLD group exhibited significantly lower bilateral volume in the lateral orbitofrontal cortex, hippocampus, accumbens area, superior temporal lobe, temporal pole, and amygdala after multiple comparison correction (p < 0.009 for all). Cortico-limbic volumes significantly improved classification of LLD beyond demographic characteristics, Aβ status, and WMH (AUCVol = 0.71, AUCWMH, Aβ = 0.62, AUC difference, 0.09 [0.03 to 0.15]). LLD exhibited poorer performance on measures of global cognition, set shifting, and verbal learning and memory relative to ND. Cognitive function was positively associated with cortico-limbic volumes and these relationships did not differ by group. Secondary analyses with an ND sample additionally matched for Mild Cognitive Impairment (MCI) diagnosis showed a similar but attenuated pattern of volume abnormalities. Overall, our results support LLD as being associated with cortico-limbic volume abnormalities that are distinct from Aβ and white matter pathologies and that these volume abnormalities are important factors associated with cognitive dysfunction in LLD.

Unveiling connections between venous disruption and cerebral small vessel disease using diffusion tensor image analysis along perivascular space (DTI-ALPS): A 7-T MRI study.

Cerebral venous disruption is one of the characteristic findings in cerebral small vessel disease (CSVD), and its disruption may impede perivascular glymphatic drainage. And lower diffusivity along perivascular space (DTI-ALPS) index has been suggested to be with the presence and severity of CSVD. However, the relationships between venous disruption, DTI-ALPS index, and CSVD neuroimaging features remain unclear. To investigate the association between venous integrity and perivascular diffusion activity, and explore the mediating role of DTI-ALPS index between venous disruption and CSVD imaging features. In this cross-sectional study, 31 patients (mean age, 59.0 ± 9.9 years) were prospectively enrolled and underwent 7-T magnetic resonance (MR) imaging. DTI-ALPS index was measured to quantify the perivascular diffusivity. The visibility and continuity of deep medullary veins (DMVs) were evaluated based on a brain region-based visual score on high-resolution susceptibility-weighted imaging. White matter hyperintensity (WMH) and perivascular space (PVS) were assessed using qualitative and quantitative methods. Linear regression and mediation analysis were performed to analyze the relationships among DMV scores, DTI-ALPS index, and CSVD features. The DTI-ALPS index was significantly associated with the parietal DMV score (β = -0.573, p corrected = 0.004). Parietal DMV score was associated with WMH volume (β = 0.463, p corrected = 0.013) and PVS volume in basal ganglia (β = 0.415, p corrected = 0.028). Mediation analyses showed that DTI-ALPS index manifested a full mediating effect on the association between parietal DMV score and WMH (indirect effect = 0.115, Pm = 43.1%), as well as between parietal DMV score and PVS volume in basal ganglia (indirect effect = 0.161, Pm = 42.8%). Cerebral venous disruption is associated with glymphatic activity, and with WMH and PVS volumes. Our results suggest cerebral venous integrity may play a critical role in preserving perivascular glymphatic activity; while disruption of small veins may impair the perivascular diffusivity, thereby contributing to the development of WMH and PVS enlargement.

Prediction of electroconvulsive therapy response and remission in late-life depression: a review.

Electroconvulsive therapy is an effective and well-tolerated antidepressant treatment for the elderly population. The place of electroconvulsive therapy in the treatment sequence for depression in the elderly is currently not well established. This review aims to identify the factors that contribute to a positive response and remission in elderly patients with depression undergoing electroconvulsive therapy treatment. We searched five bibliographic databases (Medline ALL Ovid, Embase.com, APA PsycInfo Ovid, Cochrane Library Wiley and Web of Science Core Collection) for articles published between 1995 and June 2023. Of the 2149 articles screened, 19 were included in the review. No significant associations were found between remission and/or response and salivary cortisol, baseline hippocampal and white matter hyperintensities, total amyloid load or global cortical atrophy. The reviewed articles did not show a significant difference in remission between unilateral and bilateral electroconvulsive therapy treatment. Other interesting findings are that moderately elevated levels of CRP and S100B levels, lower retardation scores, poorer performance on the word reading task at baseline and longer post-ictal reorientation time may be associated with higher remission and/or response rates. Medial temporal atrophy can be associated with lower Montgomery-Åsberg Depression Rating Scale (MADRS) decrease after electroconvulsive therapy. Finally, elderly patients had higher rates of electroconvulsive therapy response; retardation and psychotic features may mediate this association. Incorporation of this data into clinical practice may facilitate a personalised approach to electroconvulsive therapy. However, research on this topic is scarce and there are few studies that focus specifically on older people.

Characterizing the role of the microbiota-gut-brain axis in cerebral small vessel disease: An integrative multi‑omics study

BackgroundPrior efforts have revealed changes in gut microbiome, circulating metabolome, and multimodal neuroimaging features in cerebral small vessel disease (CSVD). However, there is a paucity of research integrating the multi-omic information to characterize the role of the microbiota-gut-brain axis in CSVD. MethodsWe collected gut microbiome, fecal and blood metabolome, multimodal magnetic resonance imaging data from 37 CSVD patients with white matter hyperintensities and 46 healthy controls. Between-group comparison was performed to identify the differential gut microbial taxa, followed by performance of multi-stage microbiome-metabolome-neuroimaging-neuropsychology correlation analyses in CSVD patients. ResultsOur data showed both depleted and enriched gut microbes in CSVD patients. Among the differential microbes, Haemophilus and Akkermansia were associated with a range of metabolites enriched for Aminoacyl-tRNA biosynthesis pathway. Furthermore, the affected metabolites were associated with neuroimaging measures involving gray matter morphology, spontaneous intrinsic brain activity, white matter integrity, and global structural network topology, which were in turn related to cognition and emotion in CSVD patients. ConclusionOur findings provide an integrative framework to understand the pathophysiological mechanisms underlying the interplay between gut microbiota dysbiosis and CSVD, highlighting the potential of targeting the microbiota-gut-brain axis as a therapeutic strategy in CSVD patients.

Genetic risk factors underlying white matter hyperintensities and cortical atrophy

White matter hyperintensities index structural abnormalities in the cerebral white matter, including axonal damage. The latter may promote atrophy of the cerebral cortex, a key feature of dementia. Here, we report a study of 51,065 individuals from 10 cohorts demonstrating that higher white matter hyperintensity volume associates with lower cortical thickness. The meta-GWAS of white matter hyperintensities-associated cortical ‘atrophy’ identifies 20 genome-wide significant loci, and enrichment in genes specific to vascular cell types, astrocytes, and oligodendrocytes. White matter hyperintensities-associated cortical ‘atrophy’ showed positive genetic correlations with vascular-risk traits and plasma biomarkers of neurodegeneration, and negative genetic correlations with cognitive functioning. 15 of the 20 loci regulated the expression of 54 genes in the cerebral cortex that, together with their co-expressed genes, were enriched in biological processes of axonal cytoskeleton and intracellular transport. The white matter hyperintensities-cortical thickness associations were most pronounced in cortical regions with higher expression of genes specific to excitatory neurons with long-range axons traversing through the white matter. The meta-GWAS-based polygenic risk score predicts vascular and all-cause dementia in an independent sample of 500,348 individuals. Thus, the genetics of white matter hyperintensities-related cortical atrophy involves vascular and neuronal processes and increases dementia risk.