Circulating Vascular Growth Factors and Magnetic Resonance Imaging Markers of Small Vessel Disease and Atrophy in Middle-Aged Adults.

Background and Purpose- Little is known about associations between vascular growth factors and magnetic resonance imaging (MRI) markers in midlife. We investigated the association of serum VEGF (vascular endothelial growth factor), Ang2 (angiopoietin 2), sTie2 (soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 2), and HGF (hepatocyte growth factor) concentrations with MRI markers of brain aging in middle-aged adults. Methods- We evaluated 1853 participants (mean age, 46±9 years; 46% men) from the Framingham Heart Study. Serum growth factor concentrations were measured using standardized immunoassays. Outcomes included total brain, cortical and subcortical gray matter, white matter, cerebrospinal fluid, and white matter hyperintensity volumes derived from MRI; as well as fractional anisotropy in white matter tracts from diffusion tensor imaging. We related VEGF, Ang2, sTie2, and HGF to MRI measures using multivariable regression models adjusting for vascular risk factors. We tested for interactions with APOE (apolipoprotein E) genotype and CRP (C-reactive protein). Results were corrected for multiple comparisons. Results- Higher sTie2 was associated with smaller total brain (estimate by SD unit±SE=-0.08±0.02, P=0.002) and larger white matter hyperintensity (0.08±0.02, P=0.002) volumes. Furthermore, higher Ang2 (0.06±0.02, P=0.049) and HGF (0.09±0.02, P=0.001) were associated with larger cerebrospinal fluid volumes. Finally, higher Ang2 was associated with decreased fractional anisotropy, in APOE-ε4 carriers only. Conclusions- Vascular growth factors are associated with early MRI markers of small vessel disease and neurodegeneration in middle-aged adults.

Regional T1 relaxation time constants in Ex vivo human brain: Longitudinal effects of formalin exposure.

PURPOSE: Relaxation time constants are useful as markers of tissue properties. Imaging ex vivo tissue is done for research purposes; however, T1 relaxation time constants are altered by tissue fixation in a time-dependent manner. This study investigates regional changes in T1 relaxation time constants in ex vivo brain tissue over 6 months of fixation. METHODS: Five ex vivo human brain hemispheres in 10% formalin were scanned over 6 months. Mean T1 relaxation time constants were measured in regions of interest (ROIs) representing gray matter (GM) and white matter (WM) regions and analyzed as a function of fixation time. RESULTS: Cortical GM ROIs had longer T1 relaxation time constants than WM ROIs; the thalamus had T1 relaxation time constants similar to those of WM ROIs. T1 relaxation time constants showed rapid shortening within the first 6 weeks after fixation followed by a slower rate of decline. CONCLUSION: Both GM and WM T1 relaxation time constants of fixed brain tissue show rapid decline within the first 6 weeks after autopsy and slow by 6 months. This information is useful for optimizing MR imaging acquisition parameters according to fixation time for ex vivo brain imaging studies. Magn Reson Med 77:774-778, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

An investigation of cerebrovascular lesions in dementia with Lewy bodies compared to Alzheimer's disease.

INTRODUCTION: Cerebrovascular lesions on MRI are common in Alzheimer's disease (AD) dementia, but less is known about their frequency and impact on dementia with Lewy bodies (DLB). METHODS: White-matter hyperintensities (WMHs) and infarcts on MRI were assessed in consecutive DLB (n = 81) and AD dementia (n = 240) patients and compared to age-matched and sex-matched cognitively normal subjects (CN) from a population-based cohort. RESULTS: DLB had higher WMH volume compared to CN, and WMH volume was higher in the occipital and posterior periventricular regions in DLB compared to AD. Higher WMH volume was associated with history of cardiovascular disease and diabetes but not with clinical disease severity in DLB. Frequency of infarcts in DLB was not different from CN and AD dementia. DISCUSSION: In DLB, WMH volume is higher than AD and CN and appears to be primarily associated with history of vascular disease.

Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly.

Our primary objective was to investigate a biomarker driven model for the interrelationships between vascular disease pathology, amyloid pathology, and longitudinal cognitive decline in cognitively normal elderly subjects between 70 and 90 years of age. Our secondary objective was to investigate the beneficial effect of cognitive reserve on these interrelationships. We used brain amyloid-ß load measured using Pittsburgh compound B positron emission tomography as a marker for amyloid pathology. White matter hyperintensities and brain infarcts were measured using fluid-attenuated inversion recovery magnetic resonance imaging as a marker for vascular pathology. We studied 393 cognitively normal elderly participants in the population-based Mayo Clinic Study of Aging who had a baseline 3 T fluid-attenuated inversion recovery magnetic resonance imaging assessment, Pittsburgh compound B positron emission tomography scan, baseline cognitive assessment, lifestyle measures, and at least one additional clinical follow-up. We classified subjects as being on the amyloid pathway if they had a global cortical amyloid-ß load of ≥1.5 standard uptake value ratio and those on the vascular pathway if they had a brain infarct and/or white matter hyperintensities load ≥1.11% of total intracranial volume (which corresponds to the top 25% of white matter hyperintensities in an independent non-demented sample). We used a global cognitive z-score as a measure of cognition. We found no evidence that the presence or absence of vascular pathology influenced the presence or absence of amyloid pathology and vice versa, suggesting that the two processes seem to be independent. Baseline cognitive performance was lower in older individuals, in males, those with lower education/occupation, and those on the amyloid pathway. The rate of cognitive decline was higher in older individuals (P < 0.001) and those with amyloid (P = 0.0003) or vascular (P = 0.0037) pathologies. In those subjects with both vascular and amyloid pathologies, the effect of both pathologies on cognition was additive and not synergistic. For a 79-year-old subject, the predicted annual rate of global z-score decline was -0.02 if on neither pathway, -0.07 if on the vascular pathway, -0.08 if on the amyloid pathway and -0.13 if on both pathways. The main conclusions of this study were: (i) amyloid and vascular pathologies seem to be at least partly independent processes that both affect longitudinal cognitive trajectories adversely and are major drivers of cognitive decline in the elderly; and (ii) cognitive reserve seems to offset the deleterious effect of both pathologies on the cognitive trajectories.

Insulin-Like Growth Factor, Inflammation, and MRI Markers of Alzheimer's Disease in Predominantly Middle-Aged Adults.

BACKGROUND: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults. OBJECTIVE: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation. METHODS: We included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons. RESULTS: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [ß] [95% CI], -0.05 [-0.09, -0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes. CONCLUSION: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife.

Mid-life and late-life vascular risk factor burden and neuropathology in old age.

OBJECTIVE: To determine whether vascular risk factor burden in mid- or late-life associates with postmortem vascular and neurodegenerative pathologies in a community-based sample. METHODS: We studied participants from the Framingham Heart Study who participated in our voluntary brain bank program. Overall vascular risk factor burden was calculated using the Framingham Stroke Risk Profile (FSRP). Mid-life FSRP was measured at 50 to 60 years of age. Following death, brains were autopsied and semi-quantitatively assessed by board-certified neuropathologists for cerebrovascular outcomes (cortical infarcts, subcortical infarcts, atherosclerosis, arteriosclerosis) and Alzheimer's disease pathology (Braak stage, cerebral amyloid angiopathy, and neuritic plaque score). We estimated adjusted odds ratios between vascular risk burden (at mid-life and before death) and neuropathological outcomes using logistic and proportional-odds logistic models. RESULTS: The median time interval between FSRP and death was 33.4 years for mid-life FSRP and 4.4 years for final FSRP measurement before death. Higher mid-life vascular risk burden was associated with increased odds of all cerebrovascular pathology, even with adjustment for vascular risk burden before death. Late-life vascular risk burden was associated with increased odds of cortical infarcts (OR [95% CI]: 1.04 [1.00, 1.08]) and arteriosclerosis stage (OR [95% CI]: 1.03 [1.00, 1.05]). Mid-life vascular risk burden was not associated with Alzheimer's disease pathology, though late-life vascular risk burden was associated with increased odds of higher Braak stage (OR [95% CI]: 1.03 [1.01, 1.05]). INTERPRETATION: Mid-life vascular risk burden was predictive of cerebrovascular but not Alzheimer's disease neuropathology, even after adjustment for vascular risk factors before death.

Association Between Microinfarcts and Blood Pressure Trajectories.

Importance: Cerebral microinfarcts are associated with increased risk of cognitive impairment and may have different risk factors than macroinfarcts. Subcortical microinfarcts are associated with declining blood pressure (BP) in elderly individuals. Objective: To investigate BP slopes as a risk factor for microinfarcts. Design, Setting, and Participants: From the population-based Mayo Clinic Study of Aging, 303 of 1158 individuals (26.2%) in this cohort study agreed to have an autopsy between November 1, 2004, and March 31, 2016. Cerebral microinfarcts were identified and classified as cortical or subcortical. Baseline and BP trajectories were compared for groups with no microinfarcts, subcortical microinfarcts, and cortical microinfarcts. A secondary logistic regression analysis was performed to assess associations of subcortical microinfarcts with midlife hypertension, as well as systolic and diastolic BP slopes. Main Outcomes and Measures: The presence of cerebral microinfarcts using BP slopes. Results: Of the 303 participants who underwent autopsy, 297 had antemortem BP measurements. Of these, 177 (59.6%) were men; mean (SD) age at death was 87.2 (5.3) years. The autopsied individuals and the group who died but were not autopsied were similar for all demographics except educational level with autopsied participants having a mean of 1 more year of education (1.06; 95% CI, 0.66-1.47 years; P < .01). Among 297 autopsied individuals with antemortem BP measurements, 47 (15.8%) had chronic microinfarcts; 30 (63.8%) of these participants were men. Thirty (63.8%) had cortical microinfarcts, 19 (40.4%) had subcortical microinfarcts, and 4 (8.5%) had only infratentorial microinfarcts. Participants with microinfarcts did not differ significantly on baseline systolic (mean difference, -1.48; 95% CI, -7.30 to 4.34; P = .62) and diastolic (mean difference of slope, -0.90; 95% CI, -3.93 to 2.13; P = .56) BP compared with those with no microinfarcts. However, participants with subcortical microinfarcts had a greater annual decline (negative slope) of systolic (mean difference of slope, 4.66; 95% CI, 0.13 to 9.19; P = .04) and diastolic (mean difference, 3.33; 95% CI, 0.61 to 6.06; P = .02) BP. Conclusions and Relevance: Subcortical microinfarcts were associated with declining BP. Future studies should investigate whether declining BP leads to subcortical microinfarcts or whether subcortical microinfarcts are a factor leading to declining BP.

Influence of preeclampsia and late-life hypertension on MRI measures of cortical atrophy.

OBJECTIVE: Women with a history of preeclampsia are at an increased risk of hypertension and structural brain changes. However, the combined effect of both preeclampsia and late-life hypertension on brain structural changes is not known and was investigated in this study. METHODS: Participants were identified from the population-based Rochester Epidemiology Project cohort. Four groups of women were recruited and investigated in this study: first, women with a history of normotensive pregnancy who have late-life hypertension (n = 8, median age = 62), second, women with a history of normotensive pregnancy who do not have late-life hypertension (n = 32, median age = 59), third, women with a history of preeclampsia who have late-life hypertension (n = 24, median age = 60), and fourth, women with a history of preeclampsia who do not have late-life hypertension (n = 16, median age = 57). Cerebrovascular disease lesions on MRI, and total gray matter volumes were assessed. RESULTS: Total gray matter volumes were smaller in women with a history of preeclampsia and late-life hypertension compared with the other groups. Voxel-based morphometry demonstrated that the volume changes were localized to the posterior brain regions, particularly the occipital lobe gray matter in women with a history of preeclampsia and late-life hypertension. CONCLUSION: Having late-life hypertension superimposed on a history of preeclampsia affects the brain structure differently than having either a history of preeclampsia alone or a history of normotensive pregnancy either with or without late-life hypertension.

White-matter integrity on DTI and the pathologic staging of Alzheimer's disease.

Pattern of diffusion tensor MRI (DTI) alterations were investigated in pathologically-staged Alzheimer's disease (AD) patients (n = 46). Patients with antemortem DTI studies and a range of AD pathology at autopsy were included. Patients with a high neurofibrillary tangle (NFT) stage (Braak IV-VI) had significantly elevated mean diffusivity (MD) in the crus of fornix and ventral cingulum tracts, precuneus, and entorhinal white matter on voxel-based analysis after adjusting for age and time from MRI to death (p < 0.001). Higher MD and lower fractional anisotropy in the ventral cingulum tract, entorhinal, and precuneus white matter was associated with higher Braak NFT stage and clinical disease severity. There were no MD and fractional anisotropy differences among the low (none and sparse) and high (moderate and frequent) ß-amyloid neuritic plaque groups. The NFT pathology of AD is associated with DTI alterations involving the medial temporal limbic connections and medial parietal white matter. This pattern of diffusion abnormalities is also associated with clinical disease severity.

Imaging markers of cerebrovascular pathologies: Pathophysiology, clinical presentation, and risk factors.

Cerebrovascular pathologies (CVPs) are common pathologies associated with age-related cognitive decline along with Alzheimer disease pathologies. The impact of CVP on the prevalence of dementia is increasingly being recognized. The goal of this review is to improve our understanding of the pathophysiological underpinnings and the multimodal magnetic resonance imaging and positron emission tomography imaging changes that are associated with the hallmarks of CVP. This knowledge will facilitate the development of early detection, intervention, and prevention strategies that may contribute to lowering the risk of dementia. In this review, we will first discuss currently known risk factors of CVPs including cardiovascular, lifestyle, genetic, sex differences, and head injury. Next, we will focus on the pathophysiology of CVPs and their impact on neurodegeneration and downstream cognitive impairment. Specifically, we will discuss three of the most common cerebrovascular lesions seen on MRI: white-matter hyperintensity, microbleeds, and infarcts. Finally, we will discuss the unanswered open questions in this field.

An MRI-Based Atlas for Correlation of Imaging and Pathologic Findings in Alzheimer's Disease.

BACKGROUND AND PURPOSE: Pathologic diagnosis is the gold standard in evaluating imaging measures developed as biomarkers for pathologically defined disorders. A brain MRI atlas representing autopsy-sampled tissue can be used to directly compare imaging and pathology findings. Our objective was to develop a brain MRI atlas representing the cortical regions that are routinely sampled at autopsy for the diagnosis of Alzheimer's disease (AD). METHODS: Subjects (n = 22; ages at death = 70-95) with a range of pathologies and antemortem 3T MRI were included. Histology slides from 8 cortical regions sampled from the left hemisphere at autopsy guided the localization of the atlas regions of interest (ROIs) on each subject's antemortem 3D T1 -weighted MRI. These ROIs were then registered to a common template and combined to form one ROI representing the volume of tissue that was sampled by the pathologists. A subset of the subjects (n = 4; ages at death = 79-95) had amyloid PET imaging. Density of ß-amyloid immunostain was quantified from the autopsy-sampled regions in the 4 subjects using a custom-designed ImageScope algorithm. Median uptake values were calculated in each ROI on the amyloid-PET images. RESULTS: We found an association between ß-amyloid plaque density in 8 ROIs of the 4 subjects (total ROI n = 32) and median PiB SUVR (r(2) = .64; P < .0001). CONCLUSIONS: In an atlas developed for imaging and pathologic correlation studies, we demonstrated that antemortem amyloid burden measured in the atlas ROIs on amyloid PET is strongly correlated with ß-amyloid density measured on histology. This atlas can be used in imaging and pathologic correlation studies.

Correlation of Brain Atrophy, Disability, and Spinal Cord Atrophy in a Murine Model of Multiple Sclerosis.

BACKGROUND: Disability progression in multiple sclerosis (MS) remains incompletely understood. Unlike lesional measures, central nervous system atrophy has a strong correlation with disability. Theiler's murine encephalomyelitis virus infection in SJL/J mice is an established model of progressive MS. We utilized in vivo MRI to quantify brain and spinal cord atrophy in this model and analyzed the temporal relationship between atrophy and disability. METHODS: Infected and control mice were followed for 12 months. Disability was assessed periodically using rotarod assay. Volumetric MRI datasets were acquired at 7 Tesla. Ventricular volume and C4-5 spinal cord cross-sectional area measurements were performed using Analyze 10. RESULTS: At 3 months, brain atrophy reached statistical significance (P = .005). In contrast, disability did not differ until 4 months post-infection (P = .0005). Cord atrophy reached significance by 9 months (P = 0.009). By 12 months, brain atrophy resulted in 111.8% increased ventricular volume (P = .00003), while spinal cord cross-sectional area was 25.6% reduced (P = .001) among cases. CONCLUSIONS: Our results suggest that significant brain atrophy precedes and predicts the development of disability, while spinal cord atrophy occurs late and correlates with severe disability. The observed temporal relationship establishes a framework for mechanisms of disability progression and enables further investigations of their underlying substrate.

Antemortem MRI findings associated with microinfarcts at autopsy.

OBJECTIVE: To determine antemortem MRI findings associated with microinfarcts at autopsy. METHODS: Patients with microinfarcts (n = 22) and patients without microinfarcts (n = 44) who underwent antemortem MRI were identified from a dementia clinic-based, population-based, and community clinic-based autopsy cohort. The microinfarct and no-microinfarct groups were matched on age at MRI, age at death, sex, APOE status, Mini-Mental State Examination score, and pathologic diagnosis of Alzheimer disease. Brain infarcts were assessed on fluid-attenuated inversion recovery (FLAIR) MRI. White matter hyperintensities on FLAIR MRI and hippocampal volumes on T1-weighted MRI were quantified using automated methods. A subset of subjects with microinfarcts (n = 15) and a matched group of subjects without microinfarcts (n = 15) had serial T1-weighted MRIs and were included in an analysis of global and regional brain atrophy rates using automated methods. RESULTS: The presence of cortical (p = 0.03) and subcortical (p = 0.02) infarcts on antemortem MRI was associated with presence of microinfarcts at autopsy. Higher numbers of cortical (p = 0.05) and subcortical (p = 0.03) infarcts on antemortem MRI were also associated with presence of microinfarcts. Presence of microinfarcts was not associated with white matter hyperintensities and cross-sectional hippocampal volume on antemortem MRI. Whole-brain and regional precuneus, motor, and somatosensory atrophy rates were higher in subjects with microinfarcts compared to subjects without microinfarcts. CONCLUSIONS: Microinfarcts increase brain atrophy rates independent of Alzheimer disease pathology. Association between microinfarct pathology and macroinfarcts on MRI suggests either common risk factors or a shared pathophysiology and potentially common preventive targets.

Loss of fornix white matter volume as a predictor of cognitive impairment in cognitively normal elderly individuals.

IMPORTANCE: Magnetic resonance imaging markers of incipient cognitive decline among healthy elderly individuals have become important for both clarifying the biological underpinnings of dementia and clinically identifying healthy individuals at high risk of cognitive decline. Even though the role of hippocampal atrophy is well known in the later stages of decline, the ability of fornix-hippocampal markers to predict the earliest clinical deterioration is less clear. OBJECTIVES: To examine the involvement of the hippocampus-fornix circuit in the very earliest stages of cognitive impairment and to determine whether the volumes of fornix white matter and hippocampal gray matter would be useful markers for understanding the onset of dementia and for clinical intervention. DESIGN: A longitudinal cohort of cognitively normal elderly participants received clinical evaluations with T1-weighted magnetic resonance imaging and diffusivity scans during repeated visits over an average of 4 years. Regression and Cox proportional hazards models were used to analyze the relationships between fornix and hippocampal measures and their predictive power for incidence and time of conversion from normal to impaired cognition. SETTING: A cohort of community-recruited elderly individuals at the Alzheimer Disease Center of the University of California, Davis. PARTICIPANTS: A total of 102 cognitively normal elderly participants, with an average age of 73 years, recruited through community outreach using methods designed to enhance ethnic diversity. MAIN OUTCOMES AND MEASURES: Our preliminary hypothesis was that fornix white matter volume should be a significant predictor of cognitive decline among normal elderly individuals and that fornix measures would be associated with gray matter changes in the hippocampus. RESULTS: Fornix body volume and axial diffusivity were highly significant predictors (P = .02 and .005, respectively) of cognitive decline from normal cognition. Hippocampal volume was not significant as a predictor of decline but was significantly associated with fornix volume and diffusivity (P = .004). CONCLUSIONS AND RELEVANCE: This could be among the first studies establishing fornix degeneration as a predictor of incipient cognitive decline among healthy elderly individuals. Predictive fornix volume reductions might be explained at least in part by clinically silent hippocampus degeneration. The importance of this finding is that white matter tract measures may become promising candidate biomarkers for identifying incipient cognitive decline in a clinical setting, possibly more so than traditional gray matter measures.

A conserved juxtacrine signal regulates synaptic partner recognition in Caenorhabditis elegans.

BACKGROUND: An essential stage of neural development involves the assembly of neural circuits via formation of inter-neuronal connections. Early steps in neural circuit formation, including cell migration, axon guidance, and the localization of synaptic components, are well described. However, upon reaching their target region, most neurites still contact many potential partners. In order to assemble functional circuits, it is critical that within this group of cells, neurons identify and form connections only with their appropriate partners, a process we call synaptic partner recognition (SPR). To understand how SPR is mediated, we previously developed a genetically encoded fluorescent trans-synaptic marker called NLG-1 GRASP, which labels synaptic contacts between individual neurons of interest in dense cellular environments in the genetic model organism Caenorhabditis elegans. RESULTS: Here, we describe the first use of NLG-1 GRASP technology, to identify SPR genes that function in this critical process. The NLG-1 GRASP system allows us to assess synaptogenesis between PHB sensory neurons and AVA interneurons instantly in live animals, making genetic analysis feasible. Additionally, we employ a behavioral assay to specifically test PHB sensory circuit function. Utilizing this approach, we reveal a new role for the secreted UNC-6/Netrin ligand and its transmembrane receptor UNC-40/Deleted in colorectal cancer (DCC) in SPR. Synapses between PHB and AVA are severely reduced in unc-6 and unc-40 animals despite normal axon guidance and subcellular localization of synaptic components. Additionally, behavioral defects indicate a complete disruption of PHB circuit function in unc-40 mutants. Our data indicate that UNC-40 and UNC-6 function in PHB and AVA, respectively, to specify SPR. Strikingly, overexpression of UNC-6 in postsynaptic neurons is sufficient to promote increased PHB-AVA synaptogenesis and to potentiate the behavioral response beyond wild-type levels. Furthermore, an artificially membrane-tethered UNC-6 expressed in the postsynaptic neurons promotes SPR, consistent with a short-range signal between adjacent synaptic partners. CONCLUSIONS: These results indicate that the conserved UNC-6/Netrin-UNC-40/DCC ligand-receptor pair has a previously unknown function, acting in a juxtacrine manner to specify recognition of individual postsynaptic neurons. Furthermore, they illustrate the potential of this new approach, combining NLG-1 GRASP and behavioral analysis, in gene discovery and characterization.