Leukoaraiosis and Gray Matter Volume Alteration in Older Adults: The PROOF Study

Background and Purpose: Leukoaraiosis, also called white matter hyperintensities (WMH), is frequently encountered in the brain of older adults. During aging, gray matter structure is also highly affected. WMH or gray matter defects are commonly associated with a higher prevalence of mild cognitive impairment. However, little is known about the relationship between WMH and gray matter. Our aim was thus to explore the relationship between leukoaraiosis severity and gray matter volume in a cohort of healthy older adults.Methods: Leukoaraiosis was rated in participants from the PROOF cohort using the Fazekas scale. Voxel-based morphometry was performed on brain scans to examine the potential link between WMH and changes of local brain volume. A neuropsychological evaluation including attentional, executive, and memory tests was also performed to explore cognition.Results: Out of 315 75-year-old subjects, 228 had punctuate foci of leukoaraiosis and 62 had begun the confluence of foci. Leukoaraiosis was associated with a decrease of gray matter in the middle temporal gyrus, in the right medial frontal gyrus, and in the left parahippocampal gyrus. It was also associated with decreased performances in memory recall, executive functioning, and depression.Conclusion: In a population of healthy older adults, leukoaraiosis was associated with gray matter defects and reduced cognitive performance. Controlling vascular risk factors and detecting early cerebrovascular disease may prevent, at least in part, dementia onset and progression.

Neurofilament Light Chain Is a Promising Biomarker in Alcohol Dependence

Background: Alcohol dependence, a global public health problem, leads to structural and functional damage in the brain. Alcohol dependence patients present complex and varied clinical manifestations and live with general complaints existing in contemporary society, making most people with alcohol dependence hard to identify. Therefore, it is important to find potential biomarkers for the diagnosis and evaluation of alcohol dependence. In the study, we explored potential biomarkers for the diagnosis and monitoring of diseases and evaluated brain structural changes in alcohol dependence patients.Methods: Enzyme-linked immunosorbent assay (ELSA) was employed to detect the expression of serum nucleotide-binding oligomerization domain containing 3 (NLRP3) and single-molecule array (Simoa) assay was used to detect the expression of serum neurofilament light (NfL) in 50 alcohol dependence patients and 50 controls with no drinking history. Alcohol consumption was measured by standard drinks. Neuropsychological assessments, including the Montreal cognitive assessment (MoCA), Pittsburgh sleep quality index (PSQI), generalized anxiety disorder (GAD-7), and patient health questionnaire-9 (PHQ-9), were conducted to evaluate cognitive function and psychological state. The degree of white matter lesions (WMLs) was rated using the Fazekas scale based on magnetic resonance imaging analysis. White matter structure was quantified using the voxel-based morphometry method. The correlations between NLRP3 levels, NfL levels, neuropsychological dysfunction, the degree of WMLs, and white matter volume (WMV) were analyzed in alcohol dependence patients.Results: Serum NLRP3 and NfL levels were higher in the alcohol dependence group. NLRP3 levels were irrelevant to monthly alcohol assumption as well as to the MoCA, PSQI, GAD-7, PHQ-9, and Fazekas scale scores and WMV. NfL levels were positively correlated with the PSQI and PHQ-9 scores as well as the degree of WMLs and negatively correlated with the MoCA scores and WMV. No associations were evident between NfL and monthly alcohol assumption and GAD-7 scores in the alcohol dependence group.Conclusion: This study supports the potential value of serum NfL as a non-invasive biomarker in alcohol dependence. The association with neuropsychological dysfunction and degree of WMLs has implications to use NfL as a promising biomarker to assess the severity of brain damage as well as the progression and prognosis of alcohol dependence.

Spatial Navigation Is Impaired in Elderly Patients With Cerebral Small Vessel Disease

Cerebral small vessel disease (SVD) refers to a heterogeneous group of pathological processes that result from damage to the small penetrating vessels in the brain. Spatial navigation, one of the most fundamental behaviors, has lately attracted considerable clinical interest. This study aimed to determine whether spatial navigation performance is impaired in elderly SVD patients. In total, 18 elderly patients with severe SVD, 40 elderly patients with non-severe SVD, and 41 age-matched healthy volunteers were classified according to the Fazekas scale. Spatial navigation was evaluated by Amunet (a computer-based analogy of Morris water maze software), and a mini-mental scale evaluation (MMSE), animal category verbal fluency test (VFT), clock drawing test (CDT), and trail making test (TMT) -B were also applied. Compared to healthy controls, severe SVD, rather than non-severe SVD patients, exhibited significantly worse performance on “allocentric + egocentric” (41.74 ± 29.10 vs. 31.50 ± 16.47 vs. 29.21 ± 19.03; p = 0.031). Furthermore, the different abilities of spatial navigation among groups reached a statistical level on allocentric subtests (46.93 ± 31.27 vs. 43.69 ± 23.95 vs. 28.56 ± 16.38; p = 0.003), but not on egocentric subtest (56.16 ± 39.85 vs. 56.00 ± 28.81 vs. 43.06 ± 25.07; p = 0.105). The linear regression analysis revealed that allocentric navigation deficit was significantly correlated with TMT-B (p = 0.000, standardized β = 0.342) and VFT (p = 0.016, standardized β = −0.873) performance in elderly SVD patients. These results elucidated that spatial navigation ability could be a manifestation of cognitive deficits in elderly patients with SVD.

Abstract MP13: Evaluation Of The Effect Of Low Grade Inflammation And Hypertension On The Development Of White Matter Lesions

Introduction: The risk of degenerative disease development is closely linked to persistent and continuous systemic inflammation. Although relationships between chronic low-grade inflammation (LGI) measurements and the progression of cardiovascular diseases are becoming established, the burden of the cardio-pathology and LGI on the central nervous system has not been fully investigated. Specifically, there is limited data on how hypertension (HTN) and related LGI impact white matter lesion (WML) pathogenesis. Methods: We examined 448 subjects with a mean age of 69.3 ± 7.4 years, with 62% of the cohort being women (n=276), and 45% having hypertension (n=200). Components of the LGI score included white blood cell count, albumin levels, platelet counts, and granulocyte/lymphocyte ratio, modified after. Larger LGI scores represented an increase in measured LGI intensity at that time point. MR images were obtained on a 3T system using fluid attenuation inversion recovery (FLAIR) sequence. WML burden was ascertained using Fazekas scale, done separately for both deep WML and periventricular WML. Summated score of greater than or equal to 4 was considered high overall WML burden. Results: It was found that subjects with hypertension had significantly higher LGI score when compared to subjects without hypertension after accounting for sex and BMI (F=4.8, p=0.03). Using logistic regression. we found that LGI score was related to higher WML burden (p=0.047) within the entire cohort. However, further analyses have shown that this finding was driven by the normotensive group, in which the relationship between higher WML burden and respective LGI score was significant (p=0.007). This was not the case among hypertensive subjects. Conclusion: It is clear from the data presented that a relationship between LGI and hypertension exists, confirming that inflammation is an underlying process in cardiovascular pathogenesis. However, LGI scores were related to WML in only normotensive cohorts. We offer that the effects of chronic HTN (related to higher inflammatory score itself ) overshadow the effect of LGI among hypertensive subjects. It is worth emphasizing that even in subjects without HTN white matter damage is related to LGI

Gut-Derived Metabolite Phenylacetylglutamine and White Matter Hyperintensities in Patients With Acute Ischemic Stroke

Background: White matter hyperintensity (WMH) burden is associated with a higher risk of ischemic stroke. Phenylacetylglutamine (PAGln) is a gut microbiota-derived metabolite that may induce cardiovascular events by activating platelets and increasing the risk of thrombosis. The relationship between plasma PAGln and WMH burden in patients with ischemic stroke is unknown. This study was designed to investigate the association between plasma PAGln and WMH burden in patients with acute ischemic stroke.Methods: A total of 595 patients with acute ischemic stroke were enrolled in this study within 14 days of symptom onset. The burden of WMH was evaluated using the Fazekas scale based on the fluid-attenuated inversion recovery sequence. The severity of overall WMH was defined as none–mild WMH (total Fazekas score 0–2) or moderate–severe WMH (total Fazekas score 3–6). Based on the severity of periventricular WMH (P-WMH) and deep WMH (D-WMH), patients were categorized into either a none–mild (Fazekas score 0–1) group or a moderate–severe (Fazekas score 2–3) group. Plasma PAGln levels were quantified using liquid chromatography–mass spectrometry.Results: We found that patients with moderate–severe overall WMH showed higher plasma PAGln levels than patients with none–mild overall WMH, and similar results were found in the analyses according to P-WMH and D-WMH. The logistic regression analysis showed that the fourth PAGln quartile was independently associated with moderate–severe overall WMH (adjusted 95% CI 1.134–4.018) and P-WMH (adjusted 95% CI 1.174–4.226).Conclusion: These findings suggest that higher plasma PAGln levels are associated with moderate–severe overall WMH and P-WMH in patients with acute ischemic stroke.

The Cerebellum Is Related to Cognitive Dysfunction in White Matter Hyperintensities

ObjectiveWhite matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) is frequently presumed to be secondary to cerebral small vessel disease (CSVD) and associated with cognitive decline. The cerebellum plays a key role in cognition and has dense connections with other brain regions. Thus, the aim of this study was to investigate if cerebellar abnormalities could occur in CSVD patients with WMHs and the possible association with cognitive performances.MethodsA total of 104 right-handed patients with WMHs were divided into the mild WMHs group (n = 39), moderate WMHs group (n = 37), and severe WMHs group (n = 28) according to the Fazekas scale, and 36 healthy controls were matched for sex ratio, age, education years, and acquired resting-state functional MRI. Analysis of voxel-based morphometry of gray matter volume (GMV) and seed-to-whole-brain functional connectivity (FC) was performed from the perspective of the cerebellum, and their correlations with neuropsychological variables were explored.ResultsThe analysis revealed a lower GMV in the bilateral cerebellum lobule VI and decreased FC between the left- and right-sided cerebellar lobule VI with the left anterior cingulate gyri in CSVD patients with WMHs. Both changes in structure and function were correlated with cognitive impairment in patients with WMHs.ConclusionOur study revealed damaged GMV and FC in the cerebellum associated with cognitive impairment. This indicates that the cerebellum may play a key role in the modulation of cognitive function in CSVD patients with WMHs.

Diffusion tensor imaging revealed different pathological processes of white matter hyperintensities

Background Although increasing evidence showed the correlations between white matter hyperintensities (WMHs) and cognitive impairment, the relationship between them is still modest. Many researchers began to focus on the variation caused by the heterogeneity of WMH. We tried to explore the pathological heterogeneity in WMH by using diffusion tensor imaging (DTI), so as to provide a new insight into the future research. Methods Diffusion weighted images (DWIs) of the brain were acquired from 73 patients with WMH and 18 healthy controls, which were then modeled by DTI. We measured fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of white matter of the periventricular frontal lobe (pFL), periventricular occipital lobe (pOL), periventricular parietal lobe (pPL) and deep centrum ovales (dCO), and grouped these measures according to the Fazekas scale. Then we compared the DTI metrics of different regions with the same Fazekas scale grade. Results Significantly lower FA values (all p < 0.001), and higher MD (all p < 0.001) and RD values (all p < 0.001) were associated with WMH observed in the periventricular frontal lobe (pFL) compared to all other regions with the same Fazekas grades. The AD of WMH in the pFL was higher than that of pPL and dCO, but the differences between groups was not as high as of MD and RD, as indicated by the effect size. In the normal control group, DTI metrics between pFL and other regions were not significantly different or less significant different. The difference of DTI metrics of WMH between pPL, pOL and dCO was lower than that of normal white matter, as indicated by the effect size. Conclusion Distinct pathological processes can be revealed by DTI between frontal periventricular WMH and other regions. These processes may represent the effects of severe demyelination within the frontal periventricular WMH.

Effect of Methylenetetrahydrofolate Reductase (MTHFR) gene mutations and oxidative stress in silent brain infarction

Ischemic infarctions occur under the influence of genetic and environmental factors. In our study, the role of ischemia-modified albumin and thiol balance, which are new markers in determining oxidative damage together with MTHFR gene mutations and homocysteine levels, in the development of SBI was investigated. White matter lesions in the magnetic resonance imaging (MRI) results of the patients were evaluated according to the Fazekas scale and divided into groups (Grade 0, 1, 2, and 3). Homocysteine, folate, B12, IMA, total thiol, and native thiol were measured by biochemical methods. The mutations in MTHFR genes were investigated by the RT-PCR method. According to our results, a significant difference was found between the groups in age, homocysteine, folate, IMA, total thiol, and native thiol parameters (p<0.05). When we compared the groups in terms of genotypes of the C677T gene, we found a significant difference in TT genotype between grades 0/3 and 1/3 (p<0.05). We determined that homocysteine and IMA levels increased and folate levels decreased in CC/TT and CT/TT genotypes in the C677T gene (p<0.05). Considering our results, the observation of homocysteine and IMA changes at the genotype level of the MTHFR C677T gene and between the groups, and the deterioration of thiol balance between the groups suggested that these markers can be used in the diagnosis of silent brain infarction.

Abstract P341: Cerebral Microbleeds Load and Long-Term Outcomes in Minor Ischemic Stroke

Background and Purpose: The association between the cerebral microbleed (CMB) count and outcomes in ischemic stroke has not been fully clarified. The aim of this study was to investigate the relationship between the CMB count and functional outcomes in patients with a minor ischemic stroke treated with antiplatelet therapy. Methods: Non-cardiogenic minor ischemic stroke (NIHSS score <4 on admission) patients who were treated with antiplatelet therapy were enrolled. The patients were divided into four groups based on the number of CMBs (absent, 1, 2-4, and >4), and their clinical outcomes were compared. Deep white matter hyperintensities (DWMHs) were assessed using the Fazekas scale, and the relationship between DWMH burden and the CMB count was evaluated. A poor outcome was defined as a modified Rankin scale (mRS) score of 3-6 90 days after symptom onset. Logistic regression analysis was performed to evaluate whether the CMB count contributes to poor outcomes. Results: A total of 240 patients were enrolled, and their pre mRS scores were matched based on CMB presence. The median CMB count increased linearly with the Fazekas scale grade (P<0.001). A higher burden of CMBs was linearly correlated with the rate of poor outcomes (4% in the absent group, 8% in the 1 CMB group, 13% in the 2-4 CMB group, and 20% in the >4 CMB group, P=0.002). Multivariate logistic regression analysis performed with well-known risk factors including DWMH showed that CMB burden (subgroups) was the independent factor associated with poor outcomes (odds ratio 1.75, 95% confidence interval 1.13-2.72, P=0.012), whereas the DWMH burden was not. Conclusion: The CMB count contributes independently to poor outcomes in minor ischemic stroke patients treated with antiplatelet therapy.

Multiscale Dynamics of Blood Pressure Fluctuation Is Associated With White Matter Lesion Burden in Older Adults With and Without Hypertension: Observations From a Pilot Study

Background: White matter lesions (WMLs) are highly prevalent in older adults, and hypertension is one of the main contributors to WMLs. The blood pressure (BP) is regulated by complex underlying mechanisms over multiple time scales, thus the continuous beat-to-beat BP fluctuation is complex. The association between WMLs and hypertension may be manifested as diminished complexity of BP fluctuations. The aim of this pilot study is to explore the relationships between hypertension, BP complexity, and WMLs in older adults.Method: Fifty-three older adults with clinically diagnosed hypertension and 47 age-matched older adults without hypertension completed one MRI scan and one BP recording of 10–15 min when sitting quietly. Their cerebral WMLs were assessed by two neurologists using the Fazekas scale based on brain structural MRI of each of their own. Greater score reflected higher WML grade. The complexity of continuous systolic (SBP) and diastolic (DBP) BP series was quantified using multiscale entropy (MSE). Lower MSE reflected lower complexity.Results: Compared to the non-hypertensive group, hypertensives had significantly greater Fazekas scores (F &gt; 5.3, p &lt; 0.02) and lower SBP and DBP complexity (F &gt; 8.6, p &lt; 0.004). Both within each group (β &lt; −0.42, p &lt; 0.01) and across groups (β &lt; −0.47, p &lt; 0.003), those with lower BP complexity had higher Fazekas score. Moreover, complexity of both SBP and DBP mediated the influence of hypertension on WMLs (indirect effects &gt; 0.25, 95% confidence intervals = 0.06 – 0.50).Conclusion: These results suggest that diminished BP complexity is associated with WMLs and may mediate the influence of hypertension on WMLs. Future longitudinal studies are needed to examine the causal relationship between BP complexity and WMLs.