Integrated analysis of microRNA and mRNA expression profiling identifies BAIAP3 as a novel target of dysregulated hsa-miR-1972 in age-related white matter lesions.

White matter lesions known as leukoaraiosis (LA) are cerebral white matter hyperintensities observed in elderly individuals. Currently, no reliable molecular biomarkers are available for monitoring their progression over time. To identify biomarkers for the onset and progression of LA, we analyzed whole blood-based, microRNA expression profiles of leukoaraiosis, validated those exhibiting significant microRNA changes in clinical subjects by means of quantitative real-time polymerase chain reactions and determined the function of miRNA in cell lines by means of microRNA mimic transfection assays. A total of seven microRNAs were found to be significantly down-regulated in leukoaraiosis. Among the microRNAs, hsa-miR-1972 was downregulated during the early onset phase of leukoaraiosis, as confirmed in independent patients, and it was found to target leukoaraiosis-dependent BAIAP3, decreasing its expression in 293T cell lines. Functional enrichment analysis revealed that significantly dysregulated miRNAs-mRNAs changes associated with the onset of leukoaraiosis were involved in neurogenesis, neuronal development, and differentiation. Taken together, the study identified a set of candidate microRNA biomarkers that may usefully monitor the onset and progression of leukoaraiosis. Given the enrichment of leukoaraiosis-associated microRNAs and mRNAs in neuron part and membrane system, BAIAP3 could potentially represent a novel target of hsa-miR-1972 in leukoaraiosis through which microRNAs are involved in the pathogenesis of white matter lesions.

Association of Genetic Variation in a Wnt Signaling Pathway Gene (ß-Catenin) with Susceptibility to Leukoaraiosis.

Aim: Blood-brain barrier (BBB) disruption is the primary initiating cause of cerebral small-vessel diseases including leukoaraiosis (LA). ß-Catenin is a key regulator of the BBB and plays an important role in cell-cell adhesion at adherens junctions by interacting with cadherin molecules. Thus, ß-Catenin may be a good candidate gene for LA. We performed a genetic analyses to investigate the association between ß-catenin alleles and LA. Materials and Methods: A total of 339 LA cases and 203 controls were enrolled from individuals who underwent brain magnetic resonance imaging with obtainable vascular risk factors. Genotyping of ß-catenin single nucleotide polymorphisms (SNPs), including rs1880481 C > A, rs13072632 C > T, and rs4135385 A > G, was performed by real-time polymerase chain reaction using a LightCycler 2.0. Results: Two SNPs, rs1880481 and rs4135385, showed significant differences in their allelic frequencies between the control and LA groups and the combinatorial effects of the risk alleles for these two SNPs also significantly increased the risk of LA. The G-T-A, A-T-A, and A-T-G haplotypes for the three SNPs showed significant differences in both types of LA: LA-periventricular white matter and LA-deep white matter. However, the C-T-G haplotype was only significantly different for LA-PVWM, while the A-C-A was only significantly different for LA-DWM. The combination of diabetes mellitis, hypertension, and these risk alleles increased the likelihood of both types of LA. Conclusion: This study provides evidence that ß-catenin polymorphisms and their associated haplotypes are associated with susceptibility to LA.

White matter hypointensities and hyperintensities have equivalent correlations with age and CSF ß-amyloid in the nondemented elderly.

INTRODUCTION: T1- and T2-weighted sequences from MRI often provide useful complementary information about tissue properties. Leukoaraiosis results in signal abnormalities on T1-weighted images, which are automatically quantified by FreeSurfer, but this marker is poorly characterized and is rarely used. We evaluated associations between white matter hyperintensity (WM-hyper) volume from FLAIR and white matter hypointensity (WM-hypo) volume from T1-weighted images and compared their associations with age and cerebrospinal fluid (CSF) ß-amyloid and tau. METHODS: A total of 56 nondemented participants (68-94 years) were recruited and gave informed consent. All participants went through MR imaging on a GE 1.5T scanner and of these 47 underwent lumbar puncture for CSF analysis. WM-hypo was calculated using FreeSurfer analysis of T1 FSPGR 3D, and WM-hyper was calculated with the Lesion Segmentation Toolbox in the SPM software package using T2-FLAIR. RESULTS: WM-hyper and WM-hypo were strongly correlated (r = .81; parameter estimate (p.e.): 1.53 ± 0.15; p < .0001). Age was significantly associated with both WM-hyper (r = .31, p.e. 0.078 ± 0.030, p = .013) and WM-hypo (r = .42, p.e. 0.055 ± 0.015, p < .001). CSF ß-amyloid levels were predicted by WM-hyper (r = .33, p.e. -0.11 ± 0.044, p = .013) and WM-hypo (r = .42, p.e. -0.24 ± 0.073, p = .002). CSF tau levels were not correlated with either WM-hyper (p = .9) or WM-hypo (p = .99). CONCLUSIONS: Strong correlations between WM-hyper and WM-hypo, and similar associations with age, abnormal ß-amyloid, and tau suggest a general equivalence between these two imaging markers. Our work supports the equivalence of white matter hypointensity volumes derived from FreeSurfer for evaluating leukoaraiosis. This may have particular utility when T2-FLAIR is low in quality or absent, enabling analysis of older imaging data sets.

Low-Frequency Fluctuations Amplitude Signals Exhibit Abnormalities of Intrinsic Brain Activities and Reflect Cognitive Impairment in Leukoaraiosis Patients.

BACKGROUND This study aimed to explore the amplitude of low-frequency fluctuations (ALFF) for whole-brain in leukoaraiosis (LA) patients suffering from cognitive decline or impairment. MATERIAL AND METHODS Patients were selected by employing magnetic resonance imaging (MRI) technique. According to results of the clinical dementia rating and Montreal cognitive assessment (MoCA), patients were divided into 3 groups: LA patients diagnosed as vascular mild-cognitive impairment (LA-VaMCI, n=28), LA patients diagnosed as vascular-dementia (LA-VaD, n=18), and normal individuals (NC, n=28). Executive functions were evaluated by using the Stroop test and Trail Making Test (TMT). The higher scores in TMT test mean greater impairments. Changes for the ALFF were measured by using resting-state functional MRI (rs-fMRI) technique. Correlations between ALFF and cognition scores were analyzed. RESULTS It was found that widespread differences in ALFF were present predominantly in the posterior cingulate cortex/precuneus (PCC/PCu) and in the right inferior temporal gyrus (ITG). Compared with the NC group, ALFF values in PCC/PCu were significantly decreased (F=3.273, P=0.022) and ALFF values were significantly increased (F=2.864, P=0.033) in temporal regions of the LA-VaD patients. ALFF values in LA-VaMCI patients were significantly increased in ITG compared to that in the NC group (F=1.064, P=0.042) and the LA-VaD group (F=2.725, P=0.037). Impairment in executive functions were positively correlated with average ALFF of the left PCu. CONCLUSIONS This research showed that LA patients exhibited abnormal intrinsic-brain activities. Furthermore, altered ALFF was positively correlated with executive function scores.

Oxidative Stress in Cerebral Small Vessel Disease Dizziness Patients, Basally and After Polyphenol Compound Supplementation.

BACKGROUND: Leukoaraiosis (LA) is a common radiological finding in elderly, frequently associated with several clinical disorders, including unexplained dizziness. The pathogenesis of LA is multifactorial, with a dysfunction of cerebral microcirculation resulting in chronic hypoperfusion and tissue loss, with oxidative stress involved in this cascade. OBJECTIVE: The aim of this study was to analyse some oxidative stress biomarkers in a cohort of LA patients. METHOD: Fifty-five consecutive patients (33 males, median age 75 years) with LA were recruited. In a subgroup of 33 patients with LA and unexplained dizziness, we have then performed an open study to evaluate if 60-day supplementation with a polyphenol compound may modify these biomarkers and influence quality of life, analysed with the Dizziness Handicap Inventory (DHI) scale. RESULTS: At baseline, blood oxidative stress parameters values were outside normal ranges and compared to matched healthy controls. After the two months supplementation, we observed a significant decrement of advanced oxidation protein products values and a significant improvement of DHI. CONCLUSION: Oxidative stress biomarkers may be useful to detect redox imbalance in LA and to provide non-invasive tools to monitor disease status and response to therapy.

Blood-Brain Barrier Damage as the Starting Point of Leukoaraiosis Caused by Cerebral Chronic Hypoperfusion and Its Involved Mechanisms: Effect of Agrin and Aquaporin-4.

White matter lesion (WML) is popular in the patients aged over 65. Brain edema and blood-brain barrier (BBB) dysfunction due to cerebral chronic hypoperfusion (CCH) contributed to WML. Preserving astrocyte polarity is vital for BBB integrity. In our experiment, CCH model is established by bilateral carotid arteries occlusion (2VO). Leukoaraiosis was verified by fiber density stain, and brain edema was evaluated using brain water content measuring. The expressions of agrin and aquaporin-4 (AQP4) were evaluated, as well as the integrity of BBB. Astrocyte polarity was assessed by visualizing the distribution of AQP4 on astrocyte end-feet membranes. The results showed that expression of AQP4 firstly increased and then decreased, as agrin expression decreased gradually. At 3 days after 2VO, AQP4 and agrin displayed the most opposite expression with the former increasing and the latter decreasing; at the same time, brain edema reached high point as well as BBB permeability, and astrocyte polarity was degeneration. In the later phase, brain edema and BBB permeability were getting recovered, but WML was getting more evident. In accordance with that, agrin and AQP4 expression decreased significantly with astrocyte polarity reducing. We speculated that agrin and AQP4 played key roles in development of WML by mediating BBB damage in CCH, and BBB dysfunction due to reduced astrocyte polarity is the starting point of WMH.

Association between Fibrinogen and Leukoaraiosis in Patients with Ischemic Stroke and Atrial Fibrillation.

BACKGROUND: Leukoaraiosis (LA), a surrogate of cerebral small-vessel diseases (CSVD), has been increasingly recognized because of its high prevalence and strong prognostic value in stroke. But the mechanism of LA is incompletely clarified. Fibrinogen is a crucial role in coagulation cascade and inflammation. There are inconsistent reports on the association of fibrinogen with LA in the general population. We aimed to investigate the association between fibrinogen and LA in patients with stroke and atrial fibrillation (AF), which was not ever reported before. METHODS: Patients with ischemic stroke and AF were prospectively and consecutively recruited. Clinico-demographic data and fibrinogen levels were collected within 48 hours from stroke onsets and analyzed according to the presence and distribution of LA (periventricular hyperintensity [PVH] and deep white matter hyperintensity). RESULTS: Of 186 patients (34.4% male; mean age, 68.76 ± 12.76 years) enrolled, 134 patients (72.0%) presented with LA. Elevated fibrinogen levels were associated with higher presence of LA (P = .005) and PVH (P = .002). After adjustment for the confounders, the fibrinogen levels were independently correlated with LA and PVH (all P <.05). Patients with elevated fibrinogen levels (≥3.5 g/L) were more likely to present with LA and PVH, with the odds ratios of 14.037 (95% confidence interval [CI] 2.588-76.131) and 12.567 (95% CI 2.572-61.395), respectively. CONCLUSION: This study found that fibrinogen was independently and positively associated with LA and PVH in patients with stroke and AF. These results provide further evidence for the key role of fibrinogen in LA, even the total CSVD burden.

Determinants of cerebral white matter changes in patients with stroke.

BACKGROUND/AIM: Cerebral white matter changes (WMC) are commonly observed in magnetic resonance imaging (MRI) scans of elderly people. Information about the prevalence of WMC is limited, and little is known about site-specific risk factors for the subcortical and periventricular regions in patients with ischaemic stroke. The study aims to analyse the prevalence and severity of WMC and investigate the risk factors of periventricular WMC (PVWMC) and deep WMC (DWMC) separately in patients with ischaemic stroke. METHODS: The data were collected between January and December 2013 from a medical centre in southern Taiwan. Every patient underwent a cerebral MRI scan, and WMC was separately rated as PVWMC and DWMC by using the modified Fazekas scale. RESULTS: In total, 527 patients who had experienced ischaemic stroke were included. The mean age of the patients was 67.0 ± 12.5 years (range: 31-94) and 62% of them were men. The mean age was significantly different among the four grades of severity in both the PVWMC (P < 0.001) and DWMC (P < 0.001) groups after adjustments for sex and vascular risk factors. Hypertension was independently correlated with severity of DWMC (P = 0.032) but not with PVWMC (P = 0.222). In multiple logistic regressions model, hypertension was a significant independent indicator of DWMC (odds ratio = 4.30; 95% confidence interval = 1.70-10.89). CONCLUSION: Our results suggest a region-specific pathogenesis of cerebral white matter in Asian patients with ischaemic stroke that may differ from those in the general population.

Inverse relationship between apolipoprotein A-I and cerebral white matter lesions: a cross-sectional study in middle-aged and elderly subjects.

BACKGROUND: Apolipoprotein A-I (apoA-I), the major protein for high density lipoprotein, is essential for reverse cholesterol transport. Decreased serum levels of apoA-I have been reported to correlate with subcortical infarction and dementia, both of which are highly related to white matter lesions (WMLs). However, the association between apoA-I and WMLs has never been investigated. In this study, we sought to investigate the association between apoA-I and the presence of WMLs in middle-aged and elderly subjects. METHODS: Consecutive patients aged 50 years and older of our department were prospectively enrolled in this study (n = 1282, 606 men and 676 women, 65.9 ± 9.4 years). All participants underwent MRI scans to assess the presence and severity of WMLs. Multivariate logistic regression analyses were performed to examine the association of apoA-I with WMLs. RESULTS: Patients with WMLs were older and showed significantly higher proportion of male sex, hypertension, diabetes mellitus, previous stroke, and coronary heart disease whereas levels of total cholesterol, high density lipoprotein cholesterol, and apoA-I were lower. After adjustment for potential confounders, the lowest apoA-I quartile was independently associated with an increased risk of WMLs (odds ratio: 1.87, 95% confidence interval: 1.29-2.72). In sex-specific analyses, this relationship was observed only in women. CONCLUSIONS: Our findings demonstrated that apoA-I was inversely associated with the presence of WMLs in middle-aged and elderly subjects. This results suggest that therapies which increase apoA-I concentration may be beneficial to reduce the risk of WMLs, dementia and stroke.

Heterogeneity of single small subcortical infarction can be reflected in lesion location.

Single small subcortical infarction (SSSI), also called lacunar infarction, has been regarded as a different entity with distinct pathogenesis, either lipohyalinosis and fibrinoid degeneration or atherosclerosis. The aim of our study is to identify the heterogeneity of SSSI by comparing the characteristics and imaging features according to lesion location. We retrospectively studied 203 patients with acute SSSIs (diameter ≤20 mm) demonstrated by diffusion-weighted imaging in the perforator territory of the middle cerebral artery, basilar artery, or vertebral artery. We divided the 203 patients according to the lesion location in relation to the parent artery into a distal infarction (dSSSI) group and a proximal infarction (pSSSI) group. We evaluated and compared the imaging features and clinical characteristics between the groups. The evaluated characteristics included indicators of lipohyalinosis [leukoaraiosis and silent brain infarction (SBI)], indicators of atherosclerosis [parent artery disease (PAD) and atherosclerosis of other cerebral arteries (AOCA)], lesion size, and some vascular risk factors. Between the two groups, the pSSSI group had larger lesion size, higher prevalence of PAD and AOCA, and greater frequency of diabetes mellitus, while the dSSSI group had smaller lesion size, higher prevalence of leukoaraiosis and SBI, and lower serum folic acid. Diversity of the SSSIs in imaging features and clinical characteristics according to lesion location suggests the heterogeneity of SSSIs; distal infarction is closely associated with lipohyalinosis, while proximal infarction seems to be related with atherosclerosis.

Brain iron deposition in white matter hyperintensities: a 3-T MRI study.

Iron accumulation has been implicated in the pathogenesis of demyelinating diseases. Therefore, we hypothesized that abnormal high cerebral iron deposition may be involved in the development of white matter hyperintensities (WMHs). We used R2* relaxometry to assess whether iron levels in different brain regions correlate with the severity of WMHs. This technique has been recently validated in a postmortem study to demonstrate in vivo brain iron accumulation in a quantitative manner. Fifty-two consecutive WMH patients and 30 healthy controls with 3-T magnetic resonance imaging (MRI) were reviewed in this study. We measured WMH volume (as a marker of the severity of WMHs) on MRI, and the transverse relaxation rate R2*, as an estimate of iron content in seven brain regions. We found that R2* in globus pallidus was associated with WMH volume after adjusting for sociodemographic variables (partial correlation coefficient = 0.521, P < 0.001) and in a multivariate analysis adjusted for common vascular risk factors (partial correlation coefficient = 0.572, P = 0.033). Regional R2* in globus pallidus was also significantly higher in WMHs than in controls (P = 0.042). Iron content in globus pallidus, as assessed by R2* relaxometry, is independently linked to the severity of WMHs in our cohort of patients, suggesting that iron deposition in the brain may play a role in the pathogenesis of WMHs. This may provide prognostic information on patients with WMHs and may have implications for therapeutic interventions in WMHs.

Neurochemical correlates of cognitive dysfunction in patients with leukoaraiosis: a proton magnetic resonance spectroscopy study.

OBJECTIVES: Leukoaraiosis (LA) is a common radiological finding in the elderly and may reflect cerebral small vessel disease (SVD). Although SVD has been identified as a major cause of vascular cognitive impairment or vascular dementia, the mechanisms for this association remain unclear. We therefore aimed to measure brain metabolites in LA using proton magnetic resonance spectroscopy ((1)H-MRS) as to determine the relationship between cognitive function and neurochemical white matter profile. METHODS: We recruited 23 patients with LA and 23 age- and sex-matched healthy controls consecutively. Multi-voxel (1)H-MRS was performed with a volume of interest located in centrum semiovale that contained mainly white matter voxels. Three main ratios of N-acetyl aspartate (NAA)/Cr, choline (Cho)/Cr and NAA/Cho were obtained. Spearman rank correlation coefficients were calculated between the cognitive function and the measured metabolite ratios. RESULTS: We found significantly lower levels of NAA/Cho and NAA/Cr ratios in lesioned white matter in patients with LA than healthy controls (P<0.05). The ratios of NAA/Cho and NAA/Cr in normal appearing white matter (NAWM) were higher than lesioned white matter and lower than controls, but this difference was not significant (P>0.05). There was a positive relationship between Mini-Mental State Examination (MMSE) and NAA/Cho in NAWM (r = 0.417, P = 0.048), and also a positive relationship between MMSE and NAA/Cr in lesioned white matter (r = 0.551, P = 0.006) in patients with LA. A positive relationship between the Z scores of the executive function and NAA/Cho in lesioned white matter (r = 0.557, P = 0.006) was also found. CONCLUSION: The main finding of this study was a significant reduction in the ratios of NAA/Cr and NAA/Cho in lesioned white matter, which indicates a marker of neuronal loss or dysfunction in patients with LA, which was correlated with cognitive function. This relationship between cognitive function and metabolic changes suggests that (1)H-MRS can be explored as a marker for cognitive dysfunction in patients with LA.

Brain iron dysregulation and the risk of ageing white matter lesions.

White matter lesions (WML) or leukoaraiosis is a major feature in cerebral imaging of older people, and their prevalence increases with age. The clinical effects of WML vary with the main impairment being detected in the cognitive functions, increased risk of severe depression and motor impairment. Although vascular comorbidities have been found to be the main changes in these brains, increased production of reactive oxygen species (ROS) could represent a risk factor for these lesions with elemental iron being a potential factor for ROS production. This study focuses on changes in iron, iron-regulating proteins and RNA expression of iron metabolism genes. Three groups of samples were used: WML, normal areas from lesional WM [NAWM (L)] as disease control and normal WM from control brains [NAWM(C)]. Ferric iron staining was undertaken using known Perl's reaction. Immunohistochemistry (IHC) of white matter for ceruloplasmin (Cp), haemochromatosis (HFE) and transferrin receptor (TfR) was done. Cellular localization of HFE and Cp was performed using dual-antibody IHC. Whole-genome RNA was extracted from WML, NAWM (L) and NAWM(C), and QPCR for HFE, TF, TfR, ceruloplasmin, ferritin and ferroportin was performed. Ferric iron staining shows increased diffuse iron staining among WML, followed by NAWM (L) and the least group being NAWM(C). IHC shows increased HFE and CP expression in lesional WM, while TfR shows no changes among the groups. HFE colocalized with vascular endothelium and microglia in WML and control samples, while Cp colocalized with microglia and some expression was shown by astrocytes. The mRNA expression using QPCR suggests a pattern that favours decreased intracellular iron influx, increased ferrous oxidation and increased iron export from the cells. Iron metabolism seems to be changed in brains with WML, increased elemental iron in these brains and in turn increased production of free oxidative radicals could represent a potentiating factor for the development of ageing WML.

Matrix metalloproteinases are associated with increased blood-brain barrier opening in vascular cognitive impairment.

BACKGROUND AND PURPOSE: Subcortical ischemic vascular disease (SIVD) is a major form of vascular cognitive impairment (VCI) due to small vessel disease. Matrix metalloproteinases (MMPs) are neutral proteases that disrupt the blood-brain barrier and degrade myelin basic protein under conditions of neuroinflammation. Brain tissues and cerebrospinal fluid (CSF) of patients with VCI have increased levels of MMPs. We hypothesized that patients with SIVD have increased MMPs in the CSF, which are associated with increased CSF albumin. METHODS: We studied 60 patients with suspected VCI. Twenty-five were classified as SIVD, whereas other groups included mixed Alzheimer disease and VCI, multiple strokes, and leukoaraiosis when white matter lesions were present and the diagnosis of VCI was uncertain. MMP-2 and MMP-9 in CSF and plasma were measured by gel zymography and indexed to CSF and plasma albumin. MMP-3 activity was measured by fluorescent assay. RESULTS: We found reduced MMP-2 index (P<0.001) in the CSF for the full group of patients (SIVD, multiple strokes, mixed Alzheimer disease and VCI, and leukoaraiosis) compared with control subjects, whose CSF was obtained during spinal anesthesia. MMP-3 activity was increased in VCI compared with control subjects (P<0.01). In SIVD, MMP-2 index showed a negative correlation with albumin index, which was absent with the MMP-9 index. Combining MMP-2 index and MMP-3 activity separated the patients with SIVD from the control subjects with high specificity (P<0.0005). CONCLUSIONS: Our results support the hypothesis that MMPs are associated with increased CSF albumin and suggest that they may contribute to the pathophysiology of SIVD.

Leukoaraiosis is associated with genes regulating blood-brain barrier homeostasis in ischaemic stroke patients.

BACKGROUND: The biologic agents causing leukoaraiosis are unknown. Our aim was to study the genetic basis of leukoaraiosis. METHODS: We analyzed 212 single nucleotide polymorphisms (SNPs) in 142 patients with ischaemic stroke, generating a total of 30,104 genotypes. Seventy-nine subjects (55.6%) presented leukoaraiosis measured by the Fazekas scale and 69 (48.6%) by ARWMC scale. We analyzed the presence of synergic associations between SNPs using the hfcc software. Finally, functional studies were performed in 56 subjects. The Ingenuity Pathways software (ipa) was used to examine the role of the identified genes. RESULTS: Six SNPs were associated with leukoaraiosis using both measuring scales. After logistic regression adjusted for leukoaraiosis risk factors, the rs2252070 of MMP13 (OR = 4.9, 95%CI: 1.34-17.9, P = 0.016), rs662 of PON1 (OR = 0.37, 95%CI: 0.15-0.87, P = 0.024) and rs1800779 of NOS3 (OR = 3.9, 95%CI: 1.38-11.38, P = 0.01) were independently associated with leukoaraiosis under a dominant/recessive model and the rs2290608 of IL5RA (OR = 0.46, 95%CI: 0.25-0.85, P = 0.013) and rs669 of A2M (OR = 2.5, 95%CI: 1.36-4.83, P = 0.004) under an additive model. Computational analysis showed a synergic association of rs10497212-AA of ITGB6 and rs2290608-GG of IL5RA with leukoaraiosis using both scales. (i) ARWMC (P = 1.3 × 10(-4) ) and (ii) Fazekas (P = 4.5 × 10(-5) ). Functional studies showed that the rs669 SNP was associated with plasma levels of A2M (P = 0.012) and A2M levels with leukoaraiosis in Fazekas scale (P = 0.02). ipa analysis revealed that the genes associated with leukoaraiosis were involved in blood-brain barrier (BBB) homeostasis. CONCLUSIONS: Amongst patients with ischaemic stroke, several genes associated with BBB homeostasis could be involved with a higher risk of leukoaraiosis.

Diffusion-weighted imaging and cognition in the leukoariosis and disability in the elderly study.

BACKGROUND AND PURPOSE: The mechanisms by which leukoariosis impacts on clinical and cognitive functions are not yet fully understood. We hypothesized that ultrastructural abnormalities of the normal-appearing brain tissue (NABT) assessed by diffusion-weighted imaging played a major and independent role. METHODS: In addition to a comprehensive clinical, neuropsychologic, and imaging work-up, diffusion-weighted imaging was performed in 340 participants of the multicenter leukoariosis and disability study examining the impact of white matter hyperintensities (WMH) on 65- to 85-year old individuals without previous disability. WMH severity was rated according to the Fazekas score. Multivariate regression analysis served to assess correlations of histogram metrics of the apparent diffusion coefficient (ADC) of whole-brain tissue, NABT, and of the mean ADC of WMH with cognitive functions. RESULTS: Increasing WMH scores were associated with a higher frequency of hypertension, a greater WMH volume, more brain atrophy, worse overall cognitive performance, and changes in ADC. We found strong associations between the peak height of the ADC histogram of whole-brain tissue and NABT with memory performance, executive dysfunction, and speed, which remained after adjustment for WMH lesion volume and brain atrophy and were consistent among centers. No such association was seen with the mean ADC of WMH. CONCLUSIONS: Ultrastructural abnormalities of NABT increase with WMH severity and have a strong and independent effect on cognitive functions, whereas diffusion-weighted imaging metrics within WMH have no direct impact. This should be considered when defining outcome measures for trials that attempt to ameliorate the consequences of WMH progression.

Cerebrovascular reactivity and dynamic autoregulation in ischaemic subcortical white matter disease.

BACKGROUND: It has been suggested that impaired cerebral autoregulation and vasodilatory capacity may play in role in the pathogenesis of the leukoaraiosis seen in small vessel disease. Adequate perfusion of the deep white matter of the brain depends on the relationships between blood pressure (BP), cerebral vasoreactivity and autoregulation. METHODS: 24 h ambulatory BP measurement, quantitative volumetric MRI analysis of white matter lesion (WML) volume and transcranial Doppler ultrasound assessments of CO(2) reactivity in response to hypercapnia and dynamic cerebral autoregulatory index (ARI) were undertaken in 64 patients with cerebral small vessel disease. RESULTS: Subjects had mean 24 h BP 133/76 mm Hg (SD 13/9), median WML volume 7169 (IQR 20497) mm(3), mean CO(2) reactivity 83.6 (SD 37.4)% and mean ARI 5.6 (SD 1.4) (range 0-9). In multivariate models, after adjusting for age, gender, vascular risk profile and WML volume, ARI correlated with 24 h mean BP levels (R(2) = 0.127, t = 2.440, p = 0.019) and CO(2) reactivity correlated with duration of hypertension (R(2) = 0.085, t = -2.244, p = 0.029). In individuals with hypertension for more than 10 years, ARI also correlated with nocturnal BP dipping (r = 0.806, p = 0.002). ARI and CO(2) reactivity were unaffected by WML volumes, and ARI and CO(2) reactivity were unrelated. CONCLUSION: Cerebral autoregulation and CO(2) reactivity are two distinct processes which are not related to WML volume but are related to BP levels and duration of hypertension, respectively. Greater nocturnal dipping was associated with higher ARI values, suggesting preservation of autoregulation in patients with increased vulnerability to reduced cerebral perfusion.

Age-associated leukoaraiosis and cortical cholinergic deafferentation.

OBJECTIVE: To investigate the relationship between age-associated MRI leukoaraiosis or white matter hyperintensities (WMH) and cortical acetylcholinesterase (AChE) activity. BACKGROUND: One possible mechanism of cognitive decline in elderly individuals with leukoaraiosis is disruption of cholinergic fibers by strategically located white matter lesions. Periventricular lesions may have a higher chance of disrupting cholinergic projections compared with more superficial nonperiventricular white matter lesions because of anatomic proximity to the major cholinergic axonal projection bundles that originate from the basal forebrain. METHODS: Community-dwelling, middle-aged and elderly subjects without dementia (mean age 71.0 +/- 9.2 years; 55-84 years; n = 18) underwent brain MRI and AChE PET imaging. The severity of periventricular and nonperiventricular WMH on fluid-attenuated inversion recovery MRI images was scored using the semiquantitative rating scale of Scheltens et al. [11C]methyl-4-piperidinyl propionate AChE PET imaging was used to assess cortical AChE activity. Age-corrected Spearman partial rank correlation coefficients were calculated. RESULTS: The severity of periventricular (R = -0.52, p = 0.04) but not nonperiventricular (R = -0.20, not significant) WMH was inversely related to global cortical AChE activity. Regional cortical cholinergic effects of periventricular WMH were most significant for the occipital lobe (R = -0.58, p = 0.02). CONCLUSIONS: The presence of periventricular but not nonperiventricular white matter hyperintensities (WMH) is significantly associated with lower cortical cholinergic activity. These findings support a regionally specific disruption of cholinergic projection fibers by WMH.