Biological correlates of elevated soluble TREM2 in cerebrospinal fluid

Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells-2 (sTREM2) is an emerging biomarker of neuroinflammation in Alzheimer's disease (AD). Yet, sTREM2 expression has not been systematically evaluated in relation to concomitant drivers of neuroinflammation. While associations between sTREM2 and tau in CSF are established, we sought to determine additional biological correlates of CSF sTREM2 during the prodromal stages of AD by evaluating CSF Aβ species (Aβx-40), a fluid biomarker of blood-brain barrier integrity (CSF/plasma albumin ratio), and CSF biomarkers of neurodegeneration measured in 155 participants from the Vanderbilt Memory and Aging Project. A novel association between high CSF levels of both sTREM2 and Aβx-40 was observed and replicated in an independent dataset. Aβx-40 levels, as well as the CSF/plasma albumin ratio, explained additional and unique variance in sTREM2 levels above and beyond that of CSF biomarkers of neurodegeneration. The component of sTREM2 levels correlated with Aβx-40 levels best predicted future cognitive performance. We highlight potential contributions of Aβ homeostasis and blood-brain barrier integrity to elevated CSF sTREM2, underscoring novel biomarker associations relevant to disease progression and clinical outcome measures

Evaluation of Mean Shift, ComBat, and CycleGAN for Harmonizing Brain Connectivity Matrices Across Sites

Connectivity matrices derived from diffusion MRI (dMRI) provide an interpretable and generalizable way of understanding the human brain connectome. However, dMRI suffers from inter-site and between-scanner variation, which impedes analysis across datasets to improve robustness and reproducibility of results. To evaluate different harmonization approaches on connectivity matrices, we compared graph measures derived from these matrices before and after applying three harmonization techniques: mean shift, ComBat, and CycleGAN. The sample comprises 168 age-matched, sex-matched normal subjects from two studies: the Vanderbilt Memory and Aging Project (VMAP) and the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD). First, we plotted the graph measures and used coefficient of variation (CoV) and the Mann-Whitney U test to evaluate different methods' effectiveness in removing site effects on the matrices and the derived graph measures. ComBat effectively eliminated site effects for global efficiency and modularity and outperformed the other two methods. However, all methods exhibited poor performance when harmonizing average betweenness centrality. Second, we tested whether our harmonization methods preserved correlations between age and graph measures. All methods except for CycleGAN in one direction improved correlations between age and global efficiency and between age and modularity from insignificant to significant with p-values less than 0.05.Comment: 11 pages, 5 figures, to be published in SPIE Medical Imaging 2024: Image Processin

The 12-Word Philadelphia Verbal Learning Test Performances in Older Adults: Brain MRI and Cerebrospinal Fluid Correlates and Regression-Based Normative Data

Background/Aims: This study evaluated neuroimaging and biological correlates, psychometric properties, and regression-based normative data of the 12-word Philadelphia Verbal Learning Test (PVLT), a list-learning test. Methods: Vanderbilt Memory and Aging Project participants free of clinical dementia and stroke (n = 230, aged 73 ± 7 years) completed a neuropsychological protocol and brain MRI. A subset (n = 111) underwent lumbar puncture for analysis of Alzheimer’s disease (AD) and axonal integrity cerebrospinal fluid (CSF) biomarkers. Regression models related PVLT indices to MRI and CSF biomarkers adjusting for age, sex, race/ethnicity, education, APOE-ε4 carrier status, cognitive status, and intracranial volume (MRI models). Secondary analyses were restricted to participants with normal cognition (NC; n = 127), from which regression-based normative data were generated. Results: Lower PVLT performances were associated with smaller medial temporal lobe volumes (p < 0.05) and higher CSF tau concentrations (p < 0.04). Among NC, PVLT indices were associated with white matter hyperintensities on MRI and an axonal injury biomarker (CSF neurofilament light; p < 0.03). Conclusion: The PVLT appears sensitive to markers of neurodegeneration, including temporal regions affected by AD. Conversely, in cognitively normal older adults, PVLT performance seems to relate to white matter disease and axonal injury, perhaps reflecting non-AD pathways to cognitive change. Enhanced normative data enrich the clinical utility of this tool

First published February 6

Pechman KR, Basile DP, Lund H, Mattson DL. Immune suppression blocks sodium-sensitive hypertension following recovery from ischemic acute renal failure. Am J Physiol Regul Integr Comp Physiol 294: R1234-R1239, 2008. First published February 6, 2008 doi:10.1152/ajpregu.00821.2007.-The present study determined the effect of immune suppression with mycophenolate mofetil (MMF) on sodium-sensitive hypertension following recovery from ischemia reperfusion (I/R)-induced acute renal failure. Male Sprague-Dawley rats fed 0.4% NaCl chow were subjected to 40 min bilateral I/R or control sham surgery. After 35 days of recovery, when plasma creatinine levels had returned to normal, the rats were switched to 4.0% NaCl chow for 28 days and administered vehicle or MMF (20 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ip). High-salt mean arterial pressure was significantly higher in I/R rats (144 Ϯ 16 mmHg) compared with vehicletreated sham rats (122 Ϯ 2 mmHg). Treatment of I/R rats with MMF during the period of high salt intake prevented the salt-induced increase in arterial pressure (114 Ϯ 3 mmHg). Conscious creatinine clearance was lower in I/R rats (0.27 Ϯ 0.07 ml ⅐ min Ϫ1 ⅐ 100 g body wt Ϫ1 ) compared with vehicle-treated sham rats (0.58 Ϯ 0.04 ml ⅐ min Ϫ1 ⅐ 100 g body wt Ϫ1 ); MMF treatment prevented the decrease in creatinine clearance in I/R rats (0.64 Ϯ 0.07 ml ⅐ min Ϫ1 ⅐ 100 g body wt Ϫ1 ). I/R injury also significantly increased glomerular tissue damage and increased the presence of ED-1 positive (macrophages) and S100A4 positive cells (fibroblasts) in the renal interstitium. The I/R rats treated with MMF exhibited a significant reduction in infiltrating macrophages and fibroblasts and decreased histological damage. The present data indicate that infiltrating immune cells mediate or participate in the development of sodium-sensitive hypertension and renal damage in rats apparently recovered from renal I/R injury. ischemia; hypertension; sodium dependent; rats ACUTE RENAL FAILURE (ARF) is characterized by a rapid decline of renal function that is associated with a clinical mortality rate of 50%-80% Similar to the I/R model, many models of transient or subtle renal injury result in a loss of peritubular capillaries and development of sodium-dependent hypertension (10, 12). In addition, these models of renal injury are characterized by the infiltration of macrophages, T cells, and monocytes in the renal interstitium Recent studies from our laboratory have demonstrated that the sodium-sensitive hypertension and kidney damage in the I/R recovery rats is associated with an increase in the number of fibroblasts and macrophages in the interstitial space of these kidneys (6, 21). The role of these cells in the sodium-sensitive hypertension and renal disease that occurs in rats apparently recovered from I/R injury has not been evaluated. The present studies were therefore performed to assess the influence of infiltrating immune cells in the development of sodium-dependent hypertension and renal injury in rats that have apparently recovered from I/R injury. To perform these experiments, I/R rats were permitted to recover for 5 wk from the I/R injury; the rats were then placed on a high-NaCl diet and treated with vehicle or the immune suppressive drug mycophenolate mofetil (MMF), an inhibitor of inosine 5Ј-monophosphate dehydrogenase (22, 26), for 4 wk. Indexes of salt-sensitive hypertension and renal disease were then evaluated in the control rats and those treated with the immunosuppressive agent. METHODS Animals. Male Sprague-Dawley rats were obtained from Harlan Sprague Dawley (Madison, WI). Animals were fed standard laboratory rat diet (AIN76A; Dyets, Bethlehem, PA) containing 0.4% or 4.0% NaCl, as described below; food and water were available ad libitum. Care of the rats before and during the experimental procedures was conducted in accordance with the policies of the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All protocols were approved by the Institutional Animal Care and Use Committee at the Medical College of Wisconsin. Surgical preparation and experimental protocol. To induce ARF, rats were anesthetized with ketamine (100 mg/kg ip) and pentobarbital sodium (25 mg/kg ip) and placed on a heated surgical table, and a midline incision was made. Blood supply to the kidneys was interrupted for 40 min by applying microvascular clamps on the pedicles of both kidneys. The clamps were then released, and reperfusion was visually confirmed. Additional rats were subjected to sham surgery where the kidneys were exposed but not touched. All animals were allowed to recover from I/R or sham surgery for 35 days (i.e., 5 wk post-I/R or sham surgery) while fed the 0.4% NaCl diet. Plasma creatinine measurements were obtained as an index of renal function at 24 h, 7 days, and 28 days following I/R or sham injury

Increased ANG II sensitivity following recovery from acute kidney injury: role of oxidant stress in skeletal muscle resistance arteries

Ischemia-reperfusion (I/R)-induced acute kidney injury (AKI) results in prolonged impairment of peripheral (i.e., nonrenal) vascular function since skeletal muscle resistance arteries derived from rats 5 wk post-I/R injury, show enhanced responses to ANG II stimulation but not other constrictors. Because vascular superoxide increases ANG II sensitivity, we hypothesized that peripheral responsiveness following recovery from AKI was attributable to vascular oxidant stress. Gracilis arteries (GA) isolated from post-I/R rats (∼5 wk recovery) showed significantly greater superoxide levels relative to sham-operated controls, as detected by dihydroeithidium, which was further augmented by acute ANG II stimulation in vitro. Hydrogen peroxide measured by dichlorofluorescein was not affected by ANG II. GA derived from postischemic animals manifested significantly greater constrictor responses in vitro to ANG II than GA from sham-operated controls. The addition of the superoxide scavenging reagent Tempol (10−5 M) normalized the response to values similar to sham-operated controls. Apocynin (10−6 M) and endothelial denudation nearly abrogated all ANG II-stimulated constrictor activity in GA from post-AKI rats, suggesting an important role for an endothelial-derived source of peripheral oxidative stress. Apocynin treatment in vivo abrogated GA oxidant stress and attenuated ANG II-induced pressor responses post-AKI. Interestingly, gene expression studies in GA vessels indicated a paradoxical reduction in NADPH oxidase subunit and AT1-receptor genes and no effect on several antioxidant genes. Taken together, this study demonstrates that AKI alters peripheral vascular responses by increasing oxidant stress, likely in the endothelium, via an undefined mechanism

Recovery from renal ischemia-reperfusion injury is associated with altered renal hemodynamics, blunted pressure natriuresis, and sodium-sensitive hypertension

The present studies evaluated intrarenal hemodynamics, pressure natriuresis, and arterial blood pressure in rats following recovery from renal ischemia-reperfusion (I/R) injury. Acute I/R injury, induced by 40 min of bilateral renal arterial occlusion, resulted in an increase in plasma creatinine that resolved within a week. Following 5 wk of recovery on a 0.4% NaCl diet, the pressure-natriuresis response was assessed in anesthetized rats in which the kidney was denervated and extrarenal hormones were administered intravenously. Increasing renal perfusion pressure (RPP) from 107 to 141 mmHg resulted in a fourfold increase in urine flow and sodium excretion in sham control rats. In comparison, pressure diuresis and natriuresis were significantly attenuated in post-I/R rats. In sham rats, glomerular filtration rate (GFR) averaged 1.6 ± 0.2 ml·min−1·g kidney weight−1 and renal blood flow (RBF) averaged 7.8 ± 0.7 ml·min−1·g kidney weight−1 at RPP of 129 mmHg. Renal cortical blood flow, measured by laser-Doppler flowmetry, was well autoregulated whereas medullary blood flow and renal interstitial hydrostatic pressure increased directly with elevated RPP in sham rats. In contrast, GFR and RBF were significantly reduced whereas medullary perfusion and interstitial pressure demonstrated an attenuated response to RPP in post-I/R rats. Further experiments demonstrated that conscious I/R rats develop hypertension when sodium intake is increased. The present data indicate that the pressure-natriuretic-diuretic response in I/R rats is blunted because of a decrease in GFR and RBF and the depressed pressure-dependent increase in medullary blood flow and interstitial pressure

Baseline grey matter volumes and white matter hyperintensities predict decline in functional activities in older adults over a 5-year follow-up period

Introduction: Functional independence is an essential predictor of quality of life in aging, yet few accessible predictors of functional decline have been identified. This study examined associations between baseline structural neuroimaging markers and longitudinal functional status. Methods: Linear mixed effects models with follow-up time interaction terms related baseline grey matter volume and white matter hyperintensities (WMHs) to functional trajectory, adjusting for demographic and medical covariates. Subsequent models assessed interactions with cognitive status and apolipoprotein E (APOE) ε4 status. Results: Smaller baseline grey matter volumes, particularly in regions commonly affected by Alzheimer’s disease (AD), and greater baseline WMHs were associated with faster functional decline over a mean 5-year follow-up. Effects were stronger in APOE-ε4 carriers on grey matter variables. Cognitive status interacted with most MRI variables. Discussion: Greater atrophy in AD-related regions and higher WMH burden at study entry were associated with faster functional decline, particularly among participants at increased risk of AD

White matter microstructural metrics are sensitively associated with clinical staging in Alzheimer's disease

Introduction: White matter microstructure may be abnormal along the Alzheimer's disease (AD) continuum. Methods: Diffusion magnetic resonance imaging (dMRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 627), Baltimore Longitudinal Study of Aging (BLSA, n = 684), and Vanderbilt Memory & Aging Project (VMAP, n = 296) cohorts were free-water (FW) corrected and conventional, and FW-corrected microstructural metrics were quantified within 48 white matter tracts. Microstructural values were subsequently harmonized using the Longitudinal ComBat technique and inputted as independent variables to predict diagnosis (cognitively unimpaired [CU], mild cognitive impairment [MCI], AD). Models were adjusted for age, sex, race/ethnicity, education, apolipoprotein E (APOE) ε4 carrier status, and APOE ε2 carrier status. Results: Conventional dMRI metrics were associated globally with diagnostic status; following FW correction, the FW metric itself exhibited global associations with diagnostic status, but intracellular metric associations were diminished. Discussion: White matter microstructure is altered along the AD continuum. FW correction may provide further understanding of the white matter neurodegenerative process in AD. Highlights: Longitudinal ComBat successfully harmonized large-scale diffusion magnetic resonance imaging (dMRI) metrics.Conventional dMRI metrics were globally sensitive to diagnostic status. Free-water (FW) correction mitigated intracellular associations with diagnostic status.The FW metric itself was globally sensitive to diagnostic status. Multivariate conventional and FW-corrected models may provide complementary information