Advances in Vascular Cognitive Impairment 2006

A dvances in our understanding of vascular cognitive impairment (VCI) have springboarded from further elucidation of the role of vascular risk factors, surgical procedures, medications, and neuroimaging studies that are related to this condition. The main focus of this VCI review will highlight the relation of diabetes mellitus and hippocampal dysfunction in VCI; coronary artery bypass surgery and cognitive decline; the role of cerebral amyloid angiopathy (CAA) in vascular dysfunction; and a discussion of other cardiovascular risk factors, treatment, and neuroimaging findings related to disease progression; and histopathologic and genetic correlates.

To investigate the multivariate associations among focal hemodynamic impairment, cerebral interstitial fluid accumulation (measured as free water in white matter, FW-WM), diffuse white matter injury, and cognitive decline in patients with asymptomatic unilateral severe extracranial internal carotid artery stenosis (ICAS). This study included 40 patients with asymptomatic unilateral severe extracranial ICAS and 40 matched healthy controls (HCs). All participants underwent multimodal MRI, including diffusion tensor imaging for FW-WM and FW-corrected fractional anisotropy (fwcFA), 3D-T2 FLAIR for white matter hyperintensities (WMH) volume, and arterial spin labeling for cerebral blood flow (CBF). CBF was quantified at two post-labeling delays (PLDs: 1500 ms and 2500 ms) in grey matter (GM) and, at 2500 ms, additionally in white matter (WM) of the anterior, middle, and posterior cerebral artery (ACA, MCA, PCA) territories. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA) within the patient group. Compared to HCs, patients exhibited significantly elevated global FW-WM (0.20 ± 0.03 vs. 0.18 ± 0.02, p < 0.001), reduced fwcFA (0.45 ± 0.014 vs. 0.46 ± 0.013, p = 0.017), greater WMH volume (median: 4.41 vs. 2.43 cm³, p = 0.003), and more pronounced lateralized CBF reductions in the ACA and MCA territories (all p < 0.05), indicating hemodynamic impairment. Within-patient analyses revealed a dual pathology: focal ipsilateral changes (elevated FW-WM and reduced CBF) and diffuse bilateral changes (symmetric WMH and FA reduction). After controlling for covariates, ipsilateral FW-WM correlated negatively with the lateralization index of CBF in the ACA GM (LI-CBF-ACA-GM) at PLD 1500ms and 2500ms (r = -0.464, p = 0.005 and r = -0.416, p = 0.013, respectively). Global FW-WM correlated positively with total WMH volume (r = 0.344, p = 0.043) and strongly negatively with fwcFA (r = -0.599, p < 0.001). Multivariable linear regression confirmed that FW-WM was independently associated with both ipsilateral hemodynamic impairment and global white matter injury, adjusting for age, sex, hypertension, diabetes, and homocysteine. Crucially, higher global FW-WM was associated with worse MoCA scores (r = -0.435, p = 0.007), and this association remained significant after separately adjusting for either WMH volume (partial r = -0.361, p = 0.030) or LI-CBF-ACA-GM (partial r = -0.363, p = 0.029). In asymptomatic extracranial ICAS, elevated FW‑WM integrates dual pathologies of focal hemodynamic impairment and diffuse white matter injury. Its independent association with cognitive decline positions FW-WM not only as a pivotal mechanistic link between hemodynamic compromise and clinical impairment, but also as a promising imaging biomarker. Prospective studies are warranted to validate its utility in stratifying the risk of progressive white matter injury and cognitive decline in this population.

To the Editor: The recent article by DeCarli et al1 addresses a somewhat neglected aspect of white matter hyperintensities (WMH), the significance of their anatomical location. The authors argue that the commonly accepted categorization into deep (DWMH) and periventricular (PVWMH) WMH is arbitrary, because the 2 are very highly correlated, and a spatial analysis does not reveal distinct populations. We think that this conclusion is premature, because the categorization depends on a number of factors. The first limitation of their analysis is that they examined individuals in their 70s who presented to a specialty clinic, suggesting that the white matter lesions in their sample were at an advanced stage. If an analogy is drawn from cerebral atrophy in dementia, regional differences in atrophy that are present in the different subtypes of dementia become less prominent in the later stages. In our study of WMH in middle age (60 to 64 years), the correlation of DWMH and PVWMH was much lower ( r =0.621; …

Cerebral small vessel disease is the most common cause of vascular cognitive impairment. It typically manifests with lacunar infarcts and ischaemic white matter lesions. However, little is known about how these lesions relate to the cognitive symptoms. Previous studies have found a poor correlation between the burden of ischaemic lesions and cognitive symptoms, thus leaving much of the variance in cognitive performance unexplained. The objective of the current study was to investigate the relationship between the location of subcortical ischaemic lesions and cognitive symptoms in small vessel disease. We applied a voxel-based lesion-symptom mapping approach to data from 215 patients with CADASIL, a genetically defined small vessel disease with mutations in the NOTCH3 gene. All patients were examined by magnetic resonance imaging and comprehensive neuropsychological testing. Lacunar lesions and white matter lesions were segmented on three-dimensional T(1) and fluid-attenuated inversion recovery sequences, respectively. One hundred and forty-five subjects had a total of 854 lacunar lesions (range 1-13 per individual). The normalized volume of white matter hyperintensities ranged from 0.0425% to 21.5% of the intracranial cavity. Significant clusters for cognitive performance were detected for both lacunar lesions and white matter hyperintensities. The most prominent results were obtained on a compound score for processing speed, the predominantly affected cognitive domain in this group of patients. Strategic locations included the anterior parts of the thalamus, the genu and anterior limb of the internal capsule, the anterior corona radiata and the genu of the corpus callosum. By combining the lesion-symptom mapping data with information from a probabilistic white matter atlas we found that the majority of the processing speed clusters projected on the anterior thalamic radiation and the forceps minor. In multivariate models that included demographic parameters, brain atrophy and the volume of ischaemic lesions, regional volumes of lacunar lesions and white matter hyperintensities in the anterior thalamic radiation predicted performance in processing speed tasks, whereas there was no independent contribution of the global volume of ischaemic lesions. These observations emphasize the importance of lesion location for both lacunar and ischaemic white matter lesions. Our findings further highlight the anterior thalamic radiation as a major anatomical structure impacting on processing speed. Together these findings provide strong support for a central role of frontal-subcortical circuits in cerebral small vessel disease and vascular cognitive impairment.

Vascular cognitive impairment (VCI) is a critical issue in moyamoya disease (MMD). However, the glucose metabolic pattern in these patients is still unknown. This study aimed to identify the metabolic signature of cognitive impairment in patients with MMD using 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) and establish a classifier to identify VCI in patients with MMD. One hundred fifty-two patients with MMD who underwent brain 18F-FDG PET scans before surgery were enrolled and classified into nonvascular cognitive impairment (non-VCI, n = 52) and vascular cognitive impairment (VCI, n = 100) groups according to neuropsychological test results. Additionally, thirty-three health controls (HCs) were also enrolled. Compared to HCs, patients in the VCI group exhibited extensive hypometabolism in the bilateral frontal and cingulate regions and hypermetabolism in the bilateral cerebellum, while patients in the non-VCI group showed hypermetabolism only in the cerebellum and slight hypometabolism in the frontal and temporal regions. In addition, we found that the patients in the VCI group showed hypometabolism mainly in the left basal ganglia compared to those in the non-VCI group. The sparse representation-based classifier algorithm taking the SUVr of 116 Anatomical Automatic Labeling (AAL) areas as features distinguished patients in the VCI and non-VCI groups with an accuracy of 82.4%. This study demonstrated a characteristic metabolic pattern that can distinguish patients with MMD without VCI from those with VCI, namely, hypometabolic lesions in the left hemisphere played a more important role in cognitive decline in patients with MMD.

Neural networks of the human cerebral cortex responsible for attention, memory, and emotions are modulated by cholinergic input from the 4 overlapping Ch1–Ch4 cell groups of the basal forebrain.1,2 Cholinergic neurons of the medial septal nucleus (Ch1 cell group) and the vertical limb nucleus of the diagonal band (Ch2) provide the major cholinergic input to the hippocampus. Cholinergic neurons of the horizontal limb nucleus of the diagonal band (Ch3) provide the major cholinergic input of the olfactory bulb, and cholinergic neurons of the nucleus basalis of Meynert (nbM-Ch4) provide the principal cholinergic input of the remaining cerebral cortex and amygdala. Trajectories of these cholinergic fibers in white matter have been described recently in humans.2 Cholinergic system damage leads to cognitive decline,3 thus, it is expected that the magnitude and extent of the damage will correlate with the degree of decline. White matter hyperintensities (WMHs) are encountered frequently on magnetic resonance (MR) scans of normal elderly people as well as in patients with various types of dementia. These hyperintensities are presumably related to small infarcts and lacunes caused by cerebrovascular …

One of the major recommendations emerging from the NINDS Stroke Progress Review Group was to shift the emphasis from a purely neurocentric view of cell death toward a more integrative approach whereby responses in all brain cells and matrix are considered during cerebral ischemia (see Figure). The concept of the neurovascular unit (fundamentally comprising endothelium, astrocyte, and neuron) provides a modular framework where cell-cell signaling and cell-matrix interactions mediate the overall tissue response to stroke and its treatments.1 There is no doubt that reperfusing blood vessels mechanically or pharmacologically prevents cell death and rescues brain when performed in a timely manner, as it does in ischemic myocardium. However, under some circumstances, thrombolysis and reperfusion lead to cerebral hemorrhage and edema. Here, we examine the hypothesis that beneficial versus potentially deleterious outcomes after tissue plasminogen activator (tPA) stroke therapy may relate in part to matrix proteolysis within the neurovascular unit, and review recent advances in this area. Schematic of the basic neurovascular unit showing functional interactions between neuron, astrocyte, and cerebral endothelium. This conceptual construct provides a framework for investigating the integrative response of brain to stroke and therapy. Note: ultimately, all cell types should be considered including smooth muscle cells, pericytes, as well as oligodendrocytes and axons in white matter. More than 7 years after the major ECASS and NINDS trials,2,3 use of tPA therapy remains limited.4 In part, this may be due to narrow time-to-treatment windows and apparent complications …

Cognitive Impairment in Dialysis Patients: Focus on the Blood Vessels?

Depressive Symptoms and Mild Cognitive Impairment in the Elderly: An Ominous Combination

Inflammatory biomarkers, including lipoprotein-associated phospholipase A2 (Lp-PLA2), myeloperoxidase (MPO), and high-sensitivity C-reactive protein (hsCRP) are associated with ischemic stroke risk. White matter hyperintensities (WMH) seen on brain MRI scans are associated with vascular risk factors and an increased risk of incident stroke, but their relation to inflammatory biomarkers is unclear. The Northern Manhattan Study includes a stroke-free community-based sample of Hispanic, black, and white participants with quantitative measurement of WMH volume (WMHV) and inflammatory biomarkers. We measured the association between Lp-PLA2, MPO, and hsCRP levels, and log-transformed WMHV after adjusting for sociodemographic and vascular risk factors. The hsCRP (median, 2.42 mg/L; IQR, 1.04, 5.19), Lp-PLA2 (median, 220.97 ng/mL; IQR, 185.77, 268.05), and MPO (median, 15.14 ng/mL; IQR, 12.32, 19.69) levels were available in 527 The Northern Manhattan Study participants with WMHV data but no subclinical infarcts. Those with hsCRP in the upper quartile (Q4 >4.92 mg/L or >3 mg/L), Lp-PLA2 in Q4 (>or=264.9 ng/mL), or MPO levels in Q3 (15.04-19.39 ng/mL) or Q4 (>19.39 ng/mL) each had greater WMHV, adjusting for sociodemographic and vascular risk factors. Adjusting for all biomarkers simultaneously, WMHV was 1.3-fold greater for Lp-PLA2 levels in Q4 compared to Q1 (beta=0.28; P=0.008) and 1.25-fold greater for MPO levels above the median compared to below (beta=0.22; P=0.02), but hsCRP was not associated with WMHV. Relative elevations of the inflammatory markers Lp-PLA2 and MPO were associated with a greater burden of WMH independent of hsCRP.

&lt;p dir="ltr"&gt;Specific cardiometabolic diseases (CMDs) - including type 2 diabetes, heart disease, and stroke - have been individually linked to increased risk of dementia. With population aging, a growing number of older adults are living with cardiometabolic multimorbidity - i.e., the presence of multiple, co-occurring CMDs. However, the role of cardiometabolic multimorbidity in the development of dementia is not well-understood. This thesis aimed to explore the complex interplay between cardiometabolic multimorbidity, cognitive decline, and dementia, and to identify possible compensatory factors that may attenuate the detrimental influence of CMDs on cognitive and brain health. This was carried out using data from three longitudinal studies: the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), the Screening Across the Lifespan Twin (SALT) study, and the UK Biobank (UKB).&lt;/p&gt;&lt;p dir="ltr"&gt;Study I. The relationship between CMDs and cognitive phenotypes in the preclinical/prodromal phase of dementia was examined using 12y follow-up data from SNAC-K (n=2,577). Cardiometabolic multimorbidity was associated with accelerated cognitive decline (ß -0.03 [-0.04, -0.02]) and a significantly increased risk of both cognitive impairment (HR 1.73 [1.23, 2.44]) and its progression to dementia (HR 1.86 [1.17, 2.97]).&lt;/p&gt;&lt;p dir="ltr"&gt;Study II. The association between cardiometabolic multimorbidity and dementia was assessed using 18y follow-up data from 17,913 twin individuals from SALT. Cardiometabolic multimorbidity was associated with a significantly increased risk of all-cause dementia (HR 1.42 [1.31, 1.53), Alzheimer's disease (HR 1.26 [1.10, 1.45]) and vascular dementia (HR 1.64 [1.42, 1.88]). Comparison of monozygotic and dizygotic twin pairs further indicated that genetic factors may underlie the association between CMDs and dementia.&lt;/p&gt;&lt;p dir="ltr"&gt;Study III. Cognitive reserve (characterized by higher educational and occupational attainment, social stimulation, and engagement in leisure activities) was explored as a potential compensatory factor that might attenuate the association between CMDs and dementia using 15y follow-up data from UKB (n=216,178). People with CMDs and moderate-to-high compared to low levels of cognitive reserve had 17% lower risk of dementia (HR 0.83 [0.77, 0.91]) and significantly larger volumes of gray matter and hippocampus on brain MRI.&lt;/p&gt;&lt;p dir="ltr"&gt;Study IV. The compensatory role of anti-inflammatory diet in the CMD-dementia association was examined using 15y follow-up data from UKB (n=84,342). People with CMDs and an anti-inflammatory compared to pro- inflammatory diet had 31% lower risk of dementia (HR 0.69 [0.55, 0.88]) as well as a significantly larger volume of gray matter and significantly smaller volume of white matter hyperintensities on brain MRI.&lt;/p&gt;&lt;p dir="ltr"&gt;Conclusions. Together, the findings highlight cardiometabolic multimorbidity as an especially high-risk state for a continuum of cognitive phenotypes spanning from accelerated cognitive decline to cognitive impairment and dementia. This appears to involve both neurodegenerative and vascular processes in the brain. Further, genetic background may underpin the CMD-dementia association. However, modifiable factors including high levels of cognitive reserve and adherence to an anti-inflammatory diet appear to attenuate the association between CMDs, brain pathologies, and dementia.&lt;/p&gt;&lt;p dir="ltr"&gt;Keywords: Cardiometabolic disease, dementia, Alzheimer's disease, vascular dementia, cognitive decline, brain MRI, cognitive reserve, anti-inflammatory diet, population-based study, twin study&lt;/p&gt;&lt;h3&gt;List of scientific papers&lt;/h3&gt;&lt;p dir="ltr"&gt;This thesis is based on the following original papers, which will be referred to in the text as Studies I, II, III, and IV.&lt;/p&gt;&lt;p dir="ltr"&gt;I. &lt;b&gt;Dove A,&lt;/b&gt; Marseglia A, Shang Y, Vetrano DL, Grande G, Laukka EJ, Fratiglioni L, Xu W. Cardiometabolic multimorbidity accelerates cognitive decline and dementia progression. Alzheimer's &amp; Dementia. 2022 Jun 16; 19(3): 821-830. &lt;br&gt;&lt;a href="https://doi.org/10.1002/alz.12708"&gt;https://doi.org/10.1002/alz.12708&lt;/a&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;II. &lt;b&gt;Dove A,&lt;/b&gt; Guo J, Marseglia A, Fastbom J, Vetrano DL, Fratiglioni L, Pedersen N, Xu W. Cardiometabolic multimorbidity and incident dementia: the Swedish twin registry. European Heart Journal. 2023 Feb 14; 44(7): 573-582.&lt;br&gt;&lt;a href="https://doi.org/10.1093/eurheartj/ehac744"&gt;https://doi.org/10.1093/eurheartj/ehac744&lt;/a&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;III. &lt;b&gt;Dove A,&lt;/b&gt; Yang W, Dekhtyar S, Guo J, Wang J, Marseglia A, Vetrano DL, Whitmer RA, Xu W. High cognitive reserve attenuates the risk of dementia associated with cardiometabolic diseases. Alzheimer's Research &amp; &lt;a href="https://doi.org/10.1186/s13195-024-01528-2" rel="noreferrer" target="_blank"&gt;https://doi.org/10.1186/s13195-024-01528-2&lt;/a&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;IV. &lt;b&gt;Dove A,&lt;/b&gt; Dunk MM, Wang J, Guo J, Whitmer RA, Xu W. Anti- inflammatory diet and dementia in older adults with cardiometabolic diseases. JAMA Network Open. 2024 Aug 12; 7(8): e2427125. &lt;br&gt;&lt;a href="https://doi.org/10.1001/jamanetworkopen.2024.27125"&gt;https://doi.org/10.1001/jamanetworkopen.2024.27125&lt;/a&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;br&gt;&lt;/p&gt;

Objective To explore changes and clinical significances of serum cystatin (Cys) C levels in patients with vascular cognitive impairment (VCI) after acute stroke, in order to provide evidence for early diagnosis and treatment of patients with VCI. Methods From December 2012 to December 2013, a total of 120 cases of acute stroke patients who were treated in Department of Neurology and Neurosurgery, Dongying People's Hospital were included in this study, as study group. According to whether the patients complicated VCI or not after stroke, study group were divided into VCI subgroup (n=60) and non-VCI subgroup (n=60). And at the same period, a total of 60 cases of elderly health examination who were over 50 years old and without complaints of cognitive dysfunction were included in control group (n=60). Systematic evaluations of VCI patients' cognitive function were evaluated by mini-mental state examination (MMSE) scale, and severity of VCI was divided according to results of MMSE score. Levels of serum Cys C in three group were detected with immunoturbidimetry by automatic biochemical analyzer, and relationship between serum Cys C levels and VCI severity was analyzed. The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Dongying People's Hospital. Informed consent was obtained from all participants. Results There were no significant differences in gender, age, years of education, high blood pressure, diabetes and other socio-demographic data among VCI subgroup, non-VCI subgroup and control group (P>0.05). Level of serum Cys C in VCI subgroup was (1.68±0.46) mg/L, which was higher than (0.88±0.42) mg/L of non-VCI subgroup and (0.83±0.32) mg/L of control group, and difference among three group was statistically significant (F=12.99, P<0.05). In VCI subgroup, there was statistical difference of levels of serum Cys C in patients with different VCI degrees (F=7.98, P<0.05). There were 19 cases of severe VCI patients with MMSE score ≤13 whose serum levels of Cys C were (1.92±0.36) mg/L. There were 23 cases of moderate VCI patients with MMSE score of ≥14-20 whose serum levels of Cys C were (1.33±0.41) mg/L. There were 18 cases of mild VCI patients with MMSE score of ≥21-24 whose levels of Cys C were (1.09±0.28) mg/L. There was statistical difference among above three groups (F=7.98, P<0.05). The higher levels of serum Cys C in VCI patients after acute stroke were, the more serious the degree of their VCI. The results of bivariate Spearmen correlation coefficient analysis showed that there was a negative correlation between levels of Cys C and MMSE scores in VCI patients (r=-0.421, P=0.039). Conclusions Levels of Cys C in VCI patients after acute stroke were related to their development of VCI. Levels of serum Cys C could be one of biomarkers in peripheral blood as an early diagnosis of VCI, to provide biological evidence for early diagnosis and treatment of VCI. Key words: Stroke; Cognition disorders; Diagnosis; Cystatin C

Objective To evaluate the roles of multi-voxel proton magnetic resonance spectroscopy (1H-MRS) in the early diagnosis of vascular cognitive impairment no dementia (VCIND).Methods Seventy-eight out-patients and inpatients in Department of Neurology, the second Affiliated Hospital of Soochow University from December 2008 to September 2009 were recruited in this case-control study.Their cognitive functions were assessed with a wide range of neuropsychological battery of tests including Montreal cognitive assessment ( MoCA Beijing Version ), auditory verbal learning test ( AVLT), digital span test (DST), Rey-Osterrieth complex figure test (CFT) ,semantic and phonetic fluency tests, digit symbol coding subtest (DSCT), trail making test (TMT), clock drawing test (CDT) and the Stroop color-word test (SCWT).All patients were classified into vascular cognitive impairment no dementia (VCIND) group and cognitive normal control group based on the results of neuropsychological tests.Eighteen patients with VCIND and 18 gender-, age- and education-matched normal control were randomly selected for the following study.With multi-voxel 1H-MRS, the levels of N-acetylaspartartate (NAA), creatine (Cr) and choline (Cho) in gray matters of bilateral frontal lobe, temporal lobe, parietal lobe and thalamus were measured and the ratios of NAA/Cr, Cho/Cr were compared between the two groups.Meanwhile, the correlations between scores of MoCA and its sub-items and the ratios of NAA/Cr, Cho/Cr were analyzed in VCIND group.Informed consent was obtained from all participants and the study was approved by the Ethics Committee of the hospital.Results Compared with control group, the ratios of NAA/Cr were significantly decreased in bilateral gray matters of thalamus ( left, 1.56 ± 0.49 vs 1.89 ± 0.48, F = 11.222, P = 0.002; right,1.63± 0.45 vs 1.86 ± 0.33, F = 5.358, P = 0.027 ).No significant difference were found in NAA/Cr in gray matters of bilateral frontal lobe, temporal lobe, parietal lobe and Cho/Cr in all regions between two groups ( all P ＞ 0.05 ).In VCIND group, the decreased degree of NAA/Cr in bilateral gray matters of thalamus was significantly positively correlated with the MoCA total score ( r = 0.54, 0.44 ) as well as the sub-scores in tested items of memory ( r = 0.61, 0.49 ), attention ( r = 0.43, 0.36 ), language ( r = 0.39,0.31) and visuospatial or executive( r = 0.29 , 0.33, all P＜0.05 orP＜0.01).Conclusions Cognitive impairment in patients with VCIND maybe related to metabolic dysfunction of neurons in bilateral thalamic.Multi-voxel 1H-MRS plays an important role in early diagnosis and monitoring disease progression of VCIND. Key words: Cognitive disorders; Magnetic resonance spectroscopy; Cerebrovascular disorders; Neuropsychological tests

Structural integrity of the white matter is a marker of cerebral small vessel disease, which is the major cause of vascular dementia and a quarter of all strokes. Genetic studies provide a way to obtain novel insights in the disease mechanism underlying cerebral small vessel disease. The aim was to identify common variants associated with microstructural integrity of the white matter and to elucidate the relationships of white matter structural integrity with stroke, major depressive disorder, and Alzheimer disease. This genome-wide association analysis included 8448 individuals from UK Biobank-a population-based cohort study that recruited individuals from across the United Kingdom between 2006 and 2010, aged 40 to 69 years. Microstructural integrity was measured as fractional anisotropy- (FA) and mean diffusivity (MD)-derived parameters on diffusion tensor images. White matter hyperintensity volumes (WMHV) were assessed on T2-weighted fluid-attenuated inversion recovery images. We identified 1 novel locus at genome-wide significance (VCAN [versican]: rs13164785; P=3.7×10-18 for MD and rs67827860; P=1.3×10-14 for FA). LD score regression showed a significant genome-wide correlation between FA, MD, and WMHV (FA-WMHV rG 0.39 [SE, 0.15]; MD-WMHV rG 0.56 [SE, 0.19]). In polygenic risk score analysis, FA, MD, and WMHV were significantly associated with lacunar stroke, MD with major depressive disorder, and WMHV with Alzheimer disease. Genetic variants within the VCAN gene may play a role in the mechanisms underlying microstructural integrity of the white matter in the brain measured as FA and MD. Mechanisms underlying white matter alterations are shared with cerebrovascular disease, and inherited differences in white matter microstructure impact on Alzheimer disease and major depressive disorder.

In this issue of Circulation , Jensen et al1 report that cognitive difficulties were no fewer when off-pump (OPCAB) versus conventional (CCAB) coronary artery bypass grafting was used. This important investigation, a substudy of the Best Bypass Surgery Trial, is a randomized prospective controlled trial that compares OPCAB with CCAB. Although the numbers seem relatively small (ie, 120 elderly patients with a men age of 76 years), the study was carefully powered to show differences in cognitive function at a mean of 103 days of follow-up. Although one could quibble with the details of the neuropsychological tests chosen (mini-mental state examination as a screening test for dementia after randomization but before inclusion, visual verbal learning, concept shifting, Stroop color word interference test, letter-digit coding), the main result is unequivocal. The incidence of cognitive decline was roughly 8%, and no difference between OPCAB and CCAB was found. This disappointing result raises important questions about the mechanisms of neurological injury caused by cardiac surgery and what future strategies might entail. Article p 2790 Early in the development of cardiac surgery, it was psychiatrists who first reported difficulties with thought content and process. Rizzo et al2 reported on 32 patients under the care of Lewis Dexter (cardiologist) and Dwight Harken (cardiac surgeon) who underwent “finger fracture” valvuloplasty surgery for rheumatic mitral valve disease at the Peter Bent Brigham Hospital in Boston. These psychiatrists applied analytical explanations (eg, hysterical fantasies as the heart as a sexual organ, transference to the surgeon, depersonalization, narcissism) to their findings of disordered thinking in many of their patients. Only 50 years later, these explanations sound amusingly antique, but they mark the first organized recognition that the brain could suffer serious damage as a result of cardiac surgery. The neurological complications of cardiac surgery fall into 2 …