Timing of anticoagulation for venous thromboembolism after recent traumatic and vascular brain Injury.

Currently, there is no consensus guideline for initiating anticoagulation in patients with a traumatic or vascular brain injury. Initiating anticoagulation for management of venous thromboembolism (VTE) can vary significantly from 72 hours to 30 weeks due to the risk of hemorrhagic complications. The purpose of this study is to compare clinical outcomes using modified Rankin Score (mRS) in a patient population with early (≤ 3 days) versus late (> 3 days) initiation of therapeutic anticoagulation from the time VTE was diagnosed. This retrospective study included patients with a traumatic or vascular brain injury who developed either deep vein thrombosis (DVT) or pulmonary embolism (PE). Use of anticoagulation prior to admission, diagnosis with VTE on admission, or patients with a non-brain injury were exclusion criteria. Secondary outcomes measured were all-cause mortality, length of stay, and reasons for early interruption of anticoagulation. Therapeutic anticoagulation was started early in 76 (74%) patients compared to late initiation in 27 (26%) patients. Baseline characteristics were similar between the two groups. The mRS score 0-3 versus 4-6 was similar in patients who received early anticoagulation versus those who received it later. However, there was a trend favoring better outcomes in the early group [mRS 4-6; 78% vs. 93%; p = 0.085] and in subgroup analysis of patients with VTE diagnosed 4-7 days [mRS 4-6; 26% vs. 56%; p = 0.006] compared to the late group. In univariate and multivariable logistic regression, only age was associated with a significant worse outcome (median, IQR) 36 years (24-50) vs. 58 years (44-65) OR 1.07 (1.03-1.12); p < 0.001. In this study, early initiation of anticoagulation did not worsen clinical outcomes.

Comparing Vascular Brain Injury and Stroke by Cranial Magnetic Resonance Imaging, Physician-Adjudication, and Self-Report: Data from the Strong Heart Study.

BACKGROUND: Epidemiologic studies often use self-report as proxy for clinical history. However, whether self-report correctly identifies prevalence in minority populations with health disparities and poor health-care access is unknown. Furthermore, overlap of clinical vascular events with covert vascular brain injury (VBI), detected by imaging, is largely unexamined. METHODS: The Strong Heart Study recruited American Indians from 3 regions, with surveillance and adjudication of stroke events from 1989 to 2013. In 2010-2013, all 817 survivors, aged 65-95 years, underwent brain imaging, neurological history interview, and cognitive testing. VBI was defined as imaged infarct or hemorrhage. RESULTS: Adjudicated stroke was prevalent in 4% of participants and separately collected, self-reported stroke in 8%. Imaging-defined VBI was detected in 51% and not associated with any stroke event in 47%. Compared with adjudication, self-report had 76% sensitivity and 95% specificity. Participants with adjudicated or self-reported stroke had the poorest performance on cognitive testing; those with imaging-only (covert) VBI had intermediate performance. CONCLUSION: In this community-based cohort, self-report for prior stroke had good performance metrics. A majority of participants with VBI did not have overt, clinically recognized events but did have neurological or cognitive symptoms. Data collection methodology for studies in a resource-limited setting must balance practical limitations in costs, accuracy, feasibility, and research goals.

Cognitive Correlates of MRI-defined Cerebral Vascular Injury and Atrophy in Elderly American Indians: The Strong Heart Study.

OBJECTIVE: American Indians experience substantial health disparities relative to the US population, including vascular brain aging. Poorer cognitive test performance has been associated with cranial magnetic resonance imaging findings in aging community populations, but no study has investigated these associations in elderly American Indians. METHODS: We examined 786 American Indians aged 64 years and older from the Cerebrovascular Disease and its Consequences in American Indians study (2010-2013). Cranial magnetic resonance images were scored for cortical and subcortical infarcts, hemorrhages, severity of white matter disease, sulcal widening, ventricle enlargement, and volumetric estimates for white matter hyperintensities (WMHs), hippocampus, and brain. Participants completed demographic, medical history, and neuropsychological assessments including testing for general cognitive functioning, verbal learning and memory, processing speed, phonemic fluency, and executive function. RESULTS: Processing speed was independently associated with the presence of any infarcts, white matter disease, and hippocampal and brain volumes, independent of socioeconomic, language, education, and clinical factors. Other significant associations included general cognitive functioning with hippocampal volume. Nonsignificant, marginal associations included general cognition with WMH and brain volume; verbal memory with hippocampal volume; verbal fluency and executive function with brain volume; and processing speed with ventricle enlargement. CONCLUSIONS: Brain-cognition associations found in this study of elderly American Indians are similar to those found in other racial/ethnic populations, with processing speed comprising an especially strong correlate of cerebrovascular disease. These findings may assist future efforts to define opportunities for disease prevention, to conduct research on diagnostic and normative standards, and to guide clinical evaluation of this underserved and overburdened population.

Carotid artery disease in post-stroke survivors and effects of enriched environment on stroke pathology in a mouse model of carotid artery stenosis.

AIMS: Carotid artery disease (CAD) is an important risk factor for stroke. We first evaluated CAD and stroke pathology in elderly post-stroke survivors. To simulate CAD, we assessed long-term consequences of bilateral common carotid artery stenosis (BCAS) in mice and exposed them to environmental enrichment (EE). METHODS: Histopathological methods were used to determine degrees of CAD (% area stenosis), brain infarct types, sizes and distribution in post-stroke survivors and BCAS mice. Adult male C57BL/6J mice after BCAS or sham surgery were randomly assigned to standard housing (Std) or limited (3 h) or full-time (Full) exposure to EE per day for 12 weeks. RESULTS: High frequencies of moderate carotid artery stenosis (51-75%) were evident in post-stroke survivors whereas those with severe CAD (>75% stenosis) exhibited greater numbers of cortical rather than subcortical infarcts and, were at higher risk of developing dementia. BCAS in mice reduced cerebral blood flow by 52% (P < 0.01) and thickened carotid artery walls, regardless of EE duration. Remarkably, the total and cortical infarcts declined by >50% in BCAS mice exposed to EE compared with BCAS-Std (P < 0.01). Frontal lobe and cortical strokes were associated with worsening working memory tested in a radial maze paradigm. Proteomic analysis revealed EE, both BCAS-3 h and BCAS-Full attenuated coagulation cascade factors including fibrinogen and von Willebrand factor, markers of blood-brain barrier damage. CONCLUSION: Small cortical and subcortical infarcts were evident in both post-stroke survivors with CAD and BCAS mice. Experimental evidence suggested that moderate exposure to EE is sufficient to reduce subsequent stroke lesions.

Body representation in patients after vascular brain injuries.

Neuropsychological literature suggests that body representation is a multidimensional concept consisting of various types of representations. Previous studies have demonstrated dissociations between three types of body representation specified by the kind of data and processes, i.e. body schema, body structural description, and body semantics. The aim of the study was to describe the state of body representation in patients after vascular brain injuries and to provide evidence for the different types of body representation. The question about correlations between body representation deficits and neuropsychological dysfunctions was also investigated. Fifty patients after strokes and 50 control individuals participated in the study. They were examined with tasks referring to dynamic representation of body parts positions, topological body map, and lexical and semantic knowledge about the body. Data analysis showed that vascular brain injuries result in deficits of body representation, which may co-occur with cognitive dysfunctions, but the latter are a possible risk factor for body representation deficits rather than sufficient or imperative requisites for them. The study suggests that types of body representation may be separated on the basis not only of their content, but also of their relation with self. Principal component analysis revealed three factors, which explained over 66% of results variance. The factors, which may be interpreted as types or dimensions of mental model of a body, represent different degrees of connection with self. The results indicate another possibility of body representation types classification, which should be verified in future research.

Small vessel disease and cognitive impairment: The relevance of central network connections.

Central brain network connections greatly contribute to overall network efficiency. Here we examined whether small vessel disease (SVD) related white matter alterations in central brain network connections have a greater impact on executive functioning than alterations in non-central brain network connections. Brain networks were reconstructed from diffusion-weighted MRI scans in 72 individuals (75 ± 8 years) with cognitive impairment and SVD on MRI. The centrality of white matter connections in the network was defined using graph theory. The association between the fractional anisotropy (FA) of central versus non-central connections, executive functioning, and markers of SVD was evaluated with linear regression and mediation analysis. Lower FA in central network connections was more strongly associated with impairment in executive functioning than FA in non-central network connections (r = 0.41 vs. r = 0.27; P < 0.05). Results were consistent across varying thresholds to define the central subnetwork (>50%-10% connections). Higher SVD burden was associated with lower FA in central as well as non-central network connections. However, only central network FA mediated the relationship between white matter hyperintensity volume and executive functioning [change in regression coefficient after mediation (95% CI): -0.15 (-0.35 to -0.02)]. The mediation effect was not observed for FA alterations in non-central network connections [-0.03 (-0.19 to 0.04)]. These findings suggest that the centrality of network connections, and thus their contribution to global network efficiency, appears to be relevant for understanding the relationship between SVD and cognitive impairment. Hum Brain Mapp 37:2446-2454, 2016. © 2016 Wiley Periodicals, Inc.

Blood pressure variability and risk of dementia in an elderly cohort, the Three-City Study.

BACKGROUND: The relationship between blood pressure and dementia is incompletely understood in elderly individuals. Blood pressure variability may have a role in the risk of dementia. METHODS: This investigation was a cohort study of 6506 elderly individuals followed-up for 8 years (1999-2001 through 2008) with assessments at years 2, 4, and 7-8. Blood pressure was measured by electronic devices at baseline and at 2- and 4-year follow-up examinations. Cox proportional hazard models adjusted for potential confounders were used to estimate the risk of incident dementia according to blood pressure (means and coefficients of variation of the three measures). RESULTS: During the 40,151 person-years of follow-up 474 participants developed dementia. We observed no association between mean blood pressure and risk of dementia. In contrast, an increase of 1 standard deviation in the coefficient of variation of blood pressure was associated with a 10% increased risk of dementia. Analysis by deciles of the coefficient of variation showed that the higher the variability, the higher the risk of dementia (P<.02 for trend). In the fully adjusted Cox model, the risk of dementia for those in the highest decile of the coefficient of variation of systolic blood pressure was 1.77 (1.17-2.69) compared with the lowest decile. CONCLUSIONS: In this cohort study, variability of blood pressure during follow-up was associated with an increased risk of incident dementia, whereas mean blood pressure was not. Limitation of blood pressure fluctuation may be an important target to preserve cognitive function in the elderly.

Associations between vascular health, brain stiffness and global cognitive function.

Vascular brain injury results in loss of structural and functional connectivity and leads to cognitive impairment. Its various manifestations, including microinfarcts, microhaemorrhages and white matter hyperintensities, result in microstructural tissue integrity loss and secondary neurodegeneration. Among these, tissue microstructural alteration is a relatively early event compared with atrophy along the aging and neurodegeneration continuum. Understanding its association with cognition may provide the opportunity to further elucidate the relationship between vascular health and clinical outcomes. Magnetic resonance elastography offers a non-invasive approach to evaluate tissue mechanical properties, providing a window into the microstructural integrity of the brain. This retrospective study evaluated brain stiffness as a potential biomarker for vascular brain injury and its role in mediating the impact of vascular dysfunction on cognitive impairment. Seventy-five participants from the Mayo Clinic Study of Aging underwent brain imaging using a 3T MR imager with a spin-echo echo-planar imaging sequence for magnetic resonance elastography and T1- and T2-weighted pulse sequences. This study evaluated the effects of vascular biomarkers (white matter hyperintensities and cardiometabolic condition score) on brain stiffness using voxelwise analysis. Partial correlation analysis explored associations between brain stiffness, white matter hyperintensities, cardiometabolic condition and global cognition. Mediation analysis determined the role of stiffness in mediating the relationship between vascular biomarkers and cognitive performance. Statistical significance was set at P-values < 0.05. Diagnostic accuracy of magnetic resonance elastography stiffness for white matter hyperintensities and cardiometabolic condition was evaluated using receiver operator characteristic curves. Voxelwise linear regression analysis indicated white matter hyperintensities negatively correlate with brain stiffness, specifically in periventricular regions with high white matter hyperintensity levels. A negative association between cardiovascular risk factors and stiffness was also observed across the brain. No significant patterns of stiffness changes were associated with amyloid load. Global stiffness (µ) negatively correlated with both white matter hyperintensities and cardiometabolic condition when all other covariables including amyloid load were controlled. The positive correlation between white matter hyperintensities and cardiometabolic condition weakened and became statistically insignificant when controlling for other covariables. Brain stiffness and global cognition were positively correlated, maintaining statistical significance after adjusting for all covariables. These findings suggest mechanical alterations are associated with cognitive dysfunction and vascular brain injury. Brain stiffness significantly mediated the indirect effects of white matter hyperintensities and cardiometabolic condition on global cognition. Local cerebrovascular diseases (assessed by white matter hyperintensities) and systemic vascular risk factors (assessed by cardiometabolic condition) impact brain stiffness with spatially and statistically distinct effects. Global brain stiffness is a significant mediator between vascular disease measures and cognitive function, highlighting the value of magnetic resonance elastography-based mechanical assessments in understanding this relationship.

Axenfeld-Rieger syndrome: A systematic review examining genetic, neurological, and neurovascular associations to inform screening.

Axenfeld-Rieger Syndrome (ARS) is comprised of a group of autosomal dominant disorders that are each characterized by anterior segment abnormalities of the eye. Mutations in the transcription factors FOXC1 or PITX2 are the most well-studied genetic manifestations of this syndrome. Due to the rarity this syndrome, ARS-associated neurological manifestations have not been well characterized. The purpose of this systematic review is to characterize and describe ARS neurologic manifestations that affect the cerebral vasculature and their early and late sequelae. PRISMA guidelines were followed; studies meeting inclusion criteria were analyzed for study design, evidence level, number of patients, patient age, whether the patients were related, genotype, ocular findings, and nervous system findings, specifically neurostructural and neurovascular manifestations. 63 studies met inclusion criteria, 60 (95%) were case studies or case series. The FOXC1 gene was most commonly found, followed by COL4A1, then PITX2. The most commonly described structural neurological findings were white matter abnormalities in 26 (41.3%) of studies, followed by Dandy-Walker Complex 12 (19%), and agenesis of the corpus callosum 11 (17%). Neurovascular findings were examined in 6 (9%) of studies, identifying stroke, cerebral small vessel disease (CSVD), tortuosity/dolichoectasia of arteries, among others, with no mention of moyamoya. This is the first systematic review investigating the genetic, neurological, and neurovascular associations with ARS. Structural neurological manifestations were common, yet often benign, perhaps limiting the utility of MRI screening. Neurovascular abnormalities, specifically stroke and CSVD, were identified in this population. Stroke risk was present in the presence and absence of cardiac comorbidities. These findings suggest a relationship between ARS and neurovascular findings; however, larger scale studies are necessary inform therapeutic decisions.

Plasma EFEMP1 Is Associated with Brain Aging and Dementia: The Framingham Heart Study.

BACKGROUND: Epidermal growth factor containing fibulin extracellular matrix protein-1 (EFEMP1) has been associated with increased white matter hyperintensities (WMH) burden and disorders of premature aging and may have a shared pathophysiological role in the development of WMH and dementia. OBJECTIVE: To determine the association between plasma EFEMP1 levels and MRI markers of vascular brain injury and incident all-cause and Alzheimer's disease (AD) dementia. METHODS: We measured plasma EFEMP1 levels in 1597 [53% women, mean age 68.7 (SD 5.7) years] dementia-free Framingham Offspring cohort participants between 1998-2001 and subsequently followed them for incident dementia. Secondary outcomes included stroke, structural MRI brain measures and neurocognitive test performance. RESULTS: During a median 11.8 [Q1, Q3 : 7.1, 13.3] year follow-up, 131 participants developed dementia. The highest quintile of plasma EFEMP1, compared to the bottom four quintiles, was associated with an increased risk of time to incident all-cause dementia (HR 1.77, 95% CI 1.18-2.64) and AD dementia (HR 1.76, 95% CI 1.11-2.81) but not with markers of vascular brain injury (WMH, covert brain infarcts or stroke). Higher circulating EFEMP1 concentrations were also cross-sectionally associated with lower total brain (ß±SE, -0.28±0.11, p = 0.01) and hippocampal volumes (-0.006±0.003, p = 0.04) and impaired abstract reasoning (Similarities test, -0.18±0.08, p = 0.018 per standard deviation increment in EFEMP1). CONCLUSION: Elevated circulating EFEMP1 is associated with an increased risk of all-cause and AD dementia, smaller hippocampal and total brain volumes, and poorer cognitive performance. EFEMP1 may play an important biological role in the development of AD dementia. Further studies to validate these findings are warranted.

Vascular Cognitive Impairment and cognitive decline; a longitudinal study comparing different types of vascular brain injury - The TRACE-VCI study.

Background: Little is known about the trajectories of cognitive decline in relation to different types of vascular brain injury in patients presenting at a memory clinic with Vascular Cognitive Impairment (VCI). Methods: We included 472 memory clinic patients (age 68 (±8.2) years, 44% female, MMSE 25.9 (±2.8), 210 (44.5%) dementia) from the prospective TRACE-VCI cohort study with possible VCI, defined as cognitive complaints and vascular brain injury on MRI and at least 1 follow-up cognitive assessment (follow-up time 2.5 (±1.4) years, n = 1172 assessments). Types of vascular brain injury considered lacune(s) (≥1; n = 108 patients (23%)), non-lacunar infarct(s) (≥1; n = 54 (11%)), white matter hyperintensities (WMH) (none/mild versus moderate/severe (n = 211 patients (45%)) and microbleed(s) (≥1; n = 202 patients (43%)). We assessed cognitive functioning at baseline and follow-up, including the Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT) A and B, category naming task and MMSE. The association of different types of vascular brain injury with cognitive decline was evaluated with linear mixed models, including one type of vascular brain injury (dichotomized), time and vascular brain injury*time, adjusted for sex, age, dementia status (yes/no), education (Verhage scale) and medial temporal lobe atrophy (MTA) score (dichotomized as ≥ 1.5). Results: Across the population, performance declined over time on all tests. Linear mixed models showed that lacune(s) were associated with worse baseline TMTA (Beta(SE)) (8.3 (3.8), p = .03) and TMTB (25.6 (10.3), p = .01), albeit with a slower rate of decline on MMSE, RAVLT and category naming. By contrast, patients with non-lacunar infarct(s) showed a steeper rate of decline on TMTB (29.6 (7.7), p = .00), mainly attributable to patients with dementia (62.9 (15.5), p = .00). Conclusion: Although different types of vascular brain injury have different etiologies and different patterns, they show little differences in cognitive trajectories depending on type of vascular brain injury.

Sex and Cardiovascular Function in Relation to Vascular Brain Injury in Patients with Cognitive Complaints.

BACKGROUND: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular function. OBJECTIVE: To assess the relation between sex and manifestations of vascular brain injury in patients with cognitive complaints, in interaction with cardiovascular function. METHODS: 160 outpatient clinic patients (68.8±8.5 years, 38% female) with cognitive complaints and vascular brain injury from the Heart-Brain Connection study underwent a standardized work-up, including heart-brain MRI. We calculated sex differences in vascular brain injury (lacunar infarcts, non-lacunar infarcts, white matter hyperintensities [WMHs], and microbleeds) and cardiovascular function (arterial stiffness, cardiac index, left ventricular [LV] mass index, LV mass-to-volume ratio and cerebral blood flow). In separate regression models, we analyzed the interaction effect between sex and cardiovascular function markers on manifestations of vascular brain injury with interaction terms (sex*cardiovascular function marker). RESULTS: Males had more infarcts, whereas females tended to have larger WMH-volumes. Males had higher LV mass indexes and LV mass-to-volume ratios and lower CBF values compared to females. Yet, we found no interaction effect between sex and individual cardiovascular function markers in relation to the different manifestations of vascular brain injury (p-values interaction terms > 0.05). CONCLUSION: Manifestations of vascular brain injury in patients with cognitive complaints differed by sex. There was no interaction between sex and cardiovascular function, warranting further studies to explain the observed sex differences in injury patterns.

Hypertensive Exposure Markers by MRI in Relation to Cerebral Small Vessel Disease and Cognitive Impairment.

OBJECTIVES: This study sought to investigate the extent of hypertensive exposure as assessed by cardiovascular magnetic resonance imaging (MRI) in relation to cerebral small vessel disease (CSVD) and cognitive impairment, with the aim of understanding the role of hypertension in the early stages of deteriorating brain health. BACKGROUND: Preserving brain health into advanced age is one of the great challenges of modern medicine. Hypertension is thought to induce vascular brain injury through exposure of the cerebral microcirculation to increased pressure/pulsatility. Cardiovascular MRI provides markers of (subclinical) hypertensive exposure, such as aortic stiffness by pulse wave velocity (PWV), left ventricular (LV) mass index (LVMi), and concentricity by mass-to-volume ratio. METHODS: A total of 559 participants from the Heart-Brain Connection Study (431 patients with manifest cardiovascular disease and 128 control participants), age 67.8 ± 8.8 years, underwent 3.0-T heart-brain MRI and extensive neuropsychological testing. Aortic PWV, LVMi, and LV mass-to-volume ratio were evaluated in relation to presence of CSVD and cognitive impairment. Effect modification by patient group was investigated by interaction terms; results are reported pooled or stratified accordingly. RESULTS: Aortic PWV (odds ratio [OR]: 1.17; 95% confidence interval [CI]: 1.05 to 1.30 in patient groups only), LVMi (in carotid occlusive disease, OR: 5.69; 95% CI: 1.63 to 19.87; in other groups, OR: 1.30; 95% CI: 1.05 to 1.62]) and LV mass-to-volume ratio (OR: 1.81; 95% CI: 1.46 to 2.24) were associated with CSVD. Aortic PWV (OR: 1.07; 95% CI: 1.02 to 1.13) and LV mass-to-volume ratio (OR: 1.27; 95% CI: 1.07 to 1.51) were also associated with cognitive impairment. Relations were independent of sociodemographic and cardiac index and mostly persisted after correction for systolic blood pressure or medical history of hypertension. Causal mediation analysis showed significant mediation by presence of CSVD in the relation between hypertensive exposure markers and cognitive impairment. CONCLUSIONS: The extent of hypertensive exposure is associated with CSVD and cognitive impairment beyond clinical blood pressure or medical history. The mediating role of CSVD suggests that hypertension may lead to cognitive impairment through the occurrence of CSVD.

Vascular-brain Injury Progression after Stroke (VIPS) study: concept for understanding racial and geographic determinants of cognitive decline after stroke.

Cognitive impairment and dementia (CID) are major public health problems with substantial personal, social, and financial burdens. African Americans are at a heightened risk for Vascular Cognitive Impairment (VCI) compared to European Americans. Recent lines of evidence also suggest a high burden of Post-stroke VCI among indigenous Africans. A better understanding of the cause(s) of the racial disparity in CID, specifically VCI, is needed in order to develop strategies to reduce it. We propose and discuss the conceptual framework for a unique tri-population, trans-continental study titled The Vascular brain Injury Progression after Stroke (VIPS) study. The overarching objective of the VIPS Study will be to explore the interplay of multiple factors (racial, geographical, vascular, lifestyle, nutritional, psychosocial and inflammatory) influencing the level and trajectory of post-stroke cognitive outcomes and examine whether differences between indigenous Africans, African Americans and European Americans exist. We hypothesize that differences which might be due to racial factors will be observed in African Americans versus European Americans as well as Indigenous Africans versus European Americans but not in African Americans versus Indigenous Americans; differences due to geographical factors will be observed in Indigenous Americans versus African Americans and Indigenous Africans versus European Americans but not in African Americans versus European Americans. This overarching objective could be accomplished by building upon existing National Institutes of Health investments in the REasons for Geographical And Racial Differences in Stroke (REGARDS) study (based in the United States of America) and the Stroke Investigative Research and educational Network (SIREN) study (based in Sub-Saharan Africa).

The Clinical Phenotype of Vascular Cognitive Impairment in Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) increases the risk of vascular cognitive impairment (VCI). It is unknown which type of vascular lesions and co-morbid etiologies, in particular Alzheimer's disease pathology, are associated with T2DM in patients with VCI, and how this relates to cognition and prognosis. OBJECTIVE: To compare brain MRI and cerebrospinal fluid (CSF) markers, cognition, and prognosis in patients with possible VCI with and without T2DM. METHODS: We included 851 memory clinic patients with vascular brain injury on MRI (i.e., possible VCI) from a prospective cohort study (T2DM: n = 147, 68.4±7.9 years, 63% men; no T2DM: n = 704, 67.6±8.5 years, 52% men). At baseline, we assessed between-group differences in brain MRI abnormalities, CSF markers of Alzheimer's disease, and cognitive profile. After two years follow-up, we compared occurrence of cognitive decline, stroke, and death. RESULTS: The distribution of clinical diagnoses did not differ between patients with and without T2DM. T2DM patients had more pronounced brain atrophy (total and white matter volume), and more lacunar infarcts, whereas microbleeds were less common (all p < 0.05). CSF amyloid-ß levels were similar between the groups. T2DM patients performed worse on working memory (effect size: - 0.17, p = 0.03) than those without, whereas performance on other domains was similar. During follow-up, risk of further cognitive decline was not increased in T2DM.∥Conclusion: In patients with possible VCI, presence of T2DM is related to more pronounced brain atrophy and a higher burden of lacunar infarcts, but T2DM does not have a major impact on cognitive profile or prognosis.∥.

Glioblastoma arising within sites of encephalomalacia from cerebrovascular insult: two cases and a review of the literature.

Glioblastoma is the most common primary parenchymal brain malignancy, with median survival of less than one year. While there are likely multiple predisposing genetic and environmental factors in glioblastoma formation, chronic inflammation resulting from non-traumatic vascular brain injury is one proposed risk factor for oncogenesis. Here, we report two instances of glioblastoma arising within areas of encephalomalacia caused by remote vascular insults (one following aneurysmal subarachnoid hemorrhage and one following ischemic infarction), review the literature associating glioblastoma with prior brain injury, and discuss potential mechanisms for malignant transformation in injured brain tissue.

Neuropathology correlates of cognitive assessments.

BACKGROUND: Alzheimer's disease and other dementias are the fourth largest contributors to neurological disability and the second largest contributor to deaths from neurological disease. Described in the 1980s as 'the silent epidemic' these disorders principally, though not exclusively, affect persons 80 years or older, and in developed countries, this 'old old' population continues to grow. Definitive diagnosis of the underlying cause of the neurodegenerative disease relies on neuropathological evaluation.` AIMS: Herein, we review the sampling methods, analysis and interpretation of both pathological and immunocytochemical techniques in the diagnostic assessment of neurodegenerative disease. FINDINGS: Neurodegenerative disorders are characterised by accumulation of pathologically altered protein in the human brain, and in some cases, in the peripheral tissues. Whilst it is suggested that a comprehensive review of the patient's clinical history, cognition and behaviour, together with a full clinical examination and radiological analysis, should lead to a high degree of confidence in the clinical diagnosis, the view persists that underlying pathology can only be predicted on clinical grounds especially in Alzheimer's disease, vascular brain injury and diffuse Lewy body disease with only limited accuracy. CONCLUSIONS: Neuropathological assessment of well characterised clinical cases provides accurate data on the prevalence of neurodegenerative diseases. This will aid future biomarker, neuroimaging studies and clinical trials focussed on population based cohorts.

Alzheimer's disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples.

We examined the relationships between Alzheimer's disease neuropathologic change (ADNC), Lewy body disease (LBD), and vascular brain injury (VBI) in 2 large autopsy samples. Because findings may differ between study populations, data came from U.S. Alzheimer's Disease Centers contributing to the National Alzheimer's Coordinating Center (n = 2742) and from the population-based Adult Changes in Thought study (n = 499). Regardless of study population, over 50% of participants with ADNC had co-occurring LBD or VBI; the majority of whom had a clinical AD dementia diagnosis prior to death. Overlap of pathologies was similar between studies, especially after standardizing to the distribution of age and dementia status in the Adult Changes in Thought population. LBD, but not VBI, was positively associated with ADNC in both studies. Interestingly, cortical LBD was more common in those with intermediate ADNC compared to low or high ADNC, especially in the National Alzheimer's Coordinating Center (p < 0.001). High prevalence of co-occurring neuropathologies among older adults with dementia has implications for accurate diagnosis of dementia etiologies and development of disease-modifying strategies.

Unbiased Stereological Analysis of Reactive Astrogliosis to Estimate Age-Associated Cerebral White Matter Injury.

Cerebral white matter injury (WMI) contributes to cognitive dysfunction associated with pathological aging. Because reactive astrocyte-related factors contribute to remyelination failure after WMI, we sought accurate, cost-effective, and reproducible histopathological approaches for quantification of morphometric features of reactive astrogliosis in aged human white matter in patients with vascular brain injury (VBI). We compared 7 distinct approaches to quantify the features of glial fibrillary acidic protein (GFAP)-labeled astrocytes in the prefrontal white matter of brains from patients with VBI (n = 17, mean age 88.8 years) and controls that did not exhibit VBI (n = 11, mean age 86.6 years). Only modern stereological techniques (ie, optical fractionator and spaceballs) and virtual process thickness measurements demonstrated significant changes in astrocyte number, process length, or proximal process thickness in cases with VBI relative to controls. The widely employed methods of neuropathological scoring, antibody capture assay (histelide), area fraction fractionator, and Cavalieri point counting failed to detect significant differences in GFAP expression between the groups. Unbiased stereological approaches and virtual thickness measurements provided the only sensitive and accurate means to quantify astrocyte reactivity as a surrogate marker of WMI in human brains with VBI.