Is Osteoarthritis a Vascular Disease?

Osteoarthritis (OA) is now considered as a multifaceted disease affecting various articular tissues, including cartilage, bone, synovium, and surrounding ligaments. The pathophysiology strongly implicates intricate chemical communication, primarily through cytokines, leading to the production of degradative enzymes in cartilage, inflammatory peptides in synovium, and structural changes in bone, resulting in characteristic clinical features such as joint deformities and loss of cartilage space seen on X-rays. Recent studies highlight the previously underestimated role of subchondral bone in OA, revealing its permeability to cytokines and raising questions about the influence of abnormal perfusion on OA pathophysiology, suggesting a vascular component in the disease's etiology. In essence, alterations in bone perfusion, including reduced venous outflow and intraosseous hypertension, play a crucial role in influencing the physicochemical environment of subchondral bone, impacting osteoblast cytokine expression and contributing to trabecular remodeling, changes in chondrocyte phenotype, and ultimately cartilage matrix degeneration in OA. Dynamic contrast (gadolinium) enhanced magnetic resonance imaging (DCE-MRI) was used to quantify perfusion kinetics in normal and osteoarthritic subchondral bone, demonstrating that decreased perfusion temporally precedes and spatially correlates with cartilage lesions in both young Dunkin-Hartley (D-H) guinea pigs and humans with osteoarthritis. Pharmacokinetic analysis of DCE-MRI generated data reveals decreased tracer clearance and outflow obstruction in the medial tibial plateau of osteoarthritic guinea pigs, coinciding with progressive cartilage degradation, loss of Safranin O staining, and increased expression of matrix metalloproteinases and interleukin-1. Positron emission tomographic (PET) scanning using 18F-Fluoride reveals a relationship among bone blood flow, cartilage lesions, and 18F-Fluoride influx rate in OA, highlighting the intricate relationships between decreased perfusion, altered bone metabolism, and the progression of osteoarthritis. These findings, supported by 18F-Fluoride PET data, suggest the presence of venous stasis associated with outflow obstruction, emphasizing the role of decreased subchondral bone perfusion in the pathophysiology of OA and its association with reduced osteoblast activity and advanced cartilage degeneration.

Sex-specific associations of serum cortisol with brain biomarkers of Alzheimer's risk.

Emerging evidence implicates chronic psychological stress as a risk factor for Alzheimer's disease (AD). Herein, we examined the relationships between serum cortisol and multimodality brain AD biomarkers in 277 cognitively normal midlife individuals at risk for AD. Overall, higher cortisol was associated with lower total brain volume, lower glucose metabolism (CMRglc) in frontal cortex, and higher ß-amyloid (Aß) load in AD-vulnerable regions; and marginally associated with phosphocreatine to ATP ratios (PCr/ATP) in precuneus and parietal regions. Sex-specific modification effects were noted: in women, cortisol exhibited stronger associations with Aß load and frontal CMRglc, the latter being more pronounced postmenopause. In men, cortisol exhibited stronger associations with gray matter volume and PCr/ATP measures. Higher cortisol was associated with poorer delayed memory in men but not in women. Results were adjusted for age, Apolipoprotein E (APOE) epsilon 4 status, midlife health factors, and hormone therapy use. These results suggest sex-specific neurophysiological responses to stress, and support a role for stress reduction in AD prevention.

Safety and efficacy of cerliponase alfa in children with neuronal ceroid lipofuscinosis type 2 (CLN2 disease): an open-label extension study.

BACKGROUND: Cerliponase alfa is a recombinant human tripeptidyl peptidase 1 (TPP1) enzyme replacement therapy for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2 disease), which is caused by mutations in the TPP1 gene. We aimed to determine the long-term safety and efficacy of intracerebroventricular cerliponase alfa in children with CLN2 disease. METHODS: This analysis includes cumulative data from a primary 48-week, single-arm, open-label, multicentre, dose-escalation study (NCT01907087) and the 240-week open-label extension with 6-month safety follow-up, conducted at five hospitals in Germany, Italy, the UK, and the USA. Children aged 3-16 years with CLN2 disease confirmed by genetic analysis and enzyme testing were eligible for inclusion. Treatment was intracerebroventricular infusion of 300 mg cerliponase alfa every 2 weeks. Historical controls with untreated CLN2 disease in the DEM-CHILD database were used as a comparator group. The primary efficacy outcome was time to an unreversed 2-point decline or score of 0 in the combined motor and language domains of the CLN2 Clinical Rating Scale. This extension study is registered with ClinicalTrials.gov, NCT02485899, and is complete. FINDINGS: Between Sept 13, 2013, and Dec 22, 2014, 24 participants were enrolled in the primary study (15 female and 9 male). Of those, 23 participants were enrolled in the extension study, conducted between Feb 2, 2015, and Dec 10, 2020, and received 300 mg cerliponase alfa for a mean of 272·1 (range 162·1-300·1) weeks. 17 participants completed the extension and six discontinued prematurely. Treated patients were significantly less likely than historical untreated controls to have an unreversed 2-point decline or score of 0 in the combined motor and language domains (hazard ratio 0·14, 95% CI 0·06 to 0·33; p<0·0001). All participants experienced at least one adverse event and 21 (88%) experienced a serious adverse event; nine participants experienced intracerebroventricular device-related infections, with nine events in six participants resulting in device replacement. There were no study discontinuations because of an adverse event and no deaths. INTERPRETATION: Cerliponase alfa over a mean treatment period of more than 5 years was seen to confer a clinically meaningful slowing of decline of motor and language function in children with CLN2 disease. Although our study does not have a contemporaneous control group, the results provide crucial insights into the effects of long-term treatment. FUNDING: BioMarin Pharmaceutical.

Positron Emission Tomography Quantitative Assessment of Off-Target Whole-Body Biodistribution of I-124-Labeled Adeno-Associated Virus Capsids Administered to Cerebral Spinal Fluid.

Based on studies in experimental animals demonstrating that administration of adeno-associated virus (AAV) vectors to the cerebrospinal fluid (CSF) is an effective route to transfer genes to the nervous system, there are increasing number of clinical trials using the CSF route to treat nervous system disorders. With the knowledge that the CSF turns over four to five times daily, and evidence in experimental animals that at least some of CSF administered AAV vectors are distributed to systemic organs, we asked: with AAV administration to the CSF, what fraction of the total dose remains in the nervous system and what fraction goes off target and is delivered systemically? To quantify the biodistribution of AAV capsids immediately after administration, we covalently labeled AAV capsids with iodine 124 (I-124), a cyclotron generated positron emitter, enabling quantitative positron emission tomography scanning of capsid distribution for up to 96 h after AAV vector administration. We assessed the biodistribution to nonhuman primates of I-124-labeled capsids from different AAV clades, including 9 (clade F), rh.10 (E), PHP.eB (F), hu68 (F), and rh91(A). The analysis demonstrated that 60-90% of AAV vectors administered to the CSF through either the intracisternal or intrathecal (lumbar) routes distributed systemically to major organs. These observations have potentially significant clinical implications regarding accuracy of AAV vector dosing to the nervous system, evoking systemic immunity at levels similar to that with systemic administration, and potential toxicity of genes designed to treat nervous system disorders being expressed in non-nervous system organs. Based on these data, individuals in clinical trials using AAV vectors administered to the CSF should be monitored for systemic as well as nervous system adverse events and CNS dosing considerations should account for a significant AAV systemic distribution.

Bidirectional Regulation of Motor Circuits Using Magnetogenetic Gene Therapy.

Regulating the activity of discrete neuronal populations in living mammals after delivery of modified ion channels can be used to map functional circuits and potentially treat neurological diseases. Here we report a novel suite of magnetogenetic tools, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity in motor circuits when exposed to magnetic fields. AAV-mediated delivery of a cre-dependent nanobody-TRPV1 calcium channel into the striatum of adenosine 2a (A2a) receptor-cre driver mice led to restricted expression within D2 neurons, resulting in motor freezing when placed in a 3T MRI or adjacent to a transcranial magnetic stimulation (TMS) device. Functional imaging and fiber photometry both confirmed focal activation of the target region in response to the magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing cre into the globus pallidus led to similar circuit specificity and motor responses. Finally, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in subthalamic nucleus (STN) projection neurons in PitX2-cre parkinsonian mice resulted in reduced local c-fos expression and a corresponding improvement in motor rotational behavior during magnetic field exposure. These data demonstrate that AAV delivery of magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits non-invasively in vivo using clinically available devices for both preclinical analysis of circuit effects on behavior and potential human clinical translation.

Systematic review of 31P-magnetic resonance spectroscopy studies of brain high energy phosphates and membrane phospholipids in aging and Alzheimer's disease.

Many lines of evidence suggest that mitochondria have a central role in aging-related neurodegenerative diseases, such as Alzheimer's disease (AD). Mitochondrial dysfunction, cerebral energy dysmetabolism and oxidative damage increase with age, and are early event in AD pathophysiology and may precede amyloid beta (Aß) plaques. In vivo probes of mitochondrial function and energy metabolism are therefore crucial to characterize the bioenergetic abnormalities underlying AD risk, and their relationship to pathophysiology and cognition. A majority of the research conducted in humans have used 18F-fluoro-deoxygluose (FDG) PET to image cerebral glucose metabolism (CMRglc), but key information regarding oxidative phosphorylation (OXPHOS), the process which generates 90% of the energy for the brain, cannot be assessed with this method. Thus, there is a crucial need for imaging tools to measure mitochondrial processes and OXPHOS in vivo in the human brain. 31Phosphorus-magnetic resonance spectroscopy (31P-MRS) is a non-invasive method which allows for the measurement of OXPHOS-related high-energy phosphates (HEP), including phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi), in addition to potential of hydrogen (pH), as well as components of phospholipid metabolism, such as phosphomonoesters (PMEs) and phosphodiesters (PDEs). Herein, we provide a systematic review of the existing literature utilizing the 31P-MRS methodology during the normal aging process and in patients with mild cognitive impairment (MCI) and AD, with an additional focus on individuals at risk for AD. We discuss the strengths and limitations of the technique, in addition to considering future directions toward validating the use of 31P-MRS measures as biomarkers for the early detection of AD.

Krackow Suture Technique Effect on Patella Tendon Vascularity: Quantitative MRI Analysis.

OBJECTIVES: To assess the effects of Krackow suture technique on the vascularity of the patellar tendon. METHODS: Six fresh-frozen matched pair cadaveric knee specimens were used. The superficial femoral arteries were cannulated in all knees. The experimental knee underwent an anterior approach, patellar tendon transection from the inferior pole of the patella, 4-strand Krackow stitch placement, patellar tendon repair via 3-bone tunnels, and standard skin closure. The control knee underwent the identical procedure without Krackow stitching. All specimens then underwent precontrast and postcontrast enhanced quantitative magnetic resonance imaging assessment (with gadolinium-based contrast agent). Region of interest analysis was performed to assess for variation in signal enhancement between the experimental and control limbs in various patellar tendon regions and subregions. Latex infusion and anatomical dissection were performed to further evaluate vessel integrity and assess extrinsic vascularity. RESULTS: Quantitative magnetic resonance imaging analysis demonstrated no statistically significant difference in overall arterial contributions. A small but nonsignificant decrease of 7.5% (SD ± 7.1%) in arterial contributions to the entire tendon was observed. Small nonstatistically significant regional decreases throughout the tendon were also detected. In the regional analysis, the largest to smallest decreases in arterial contributions after suture placement were found in the inferomedial, superolateral, lateral, and inferior tendon subregions. In the anatomical dissection, nutrient branches were seen dorsally and posteroinferiorly. CONCLUSION: The vascularity of the patellar tendon was not significantly affected by Krackow suture placement. Analysis demonstrated small and not statistically significant decreases in arterial contributions, suggesting this technique does not significantly compromise arterial perfusion.

Cerebral oxygen extraction fraction declines with ventricular enlargement in patients with normal pressure hydrocephalus.

OBJECTIVE: Normal pressure hydrocephalus (NPH) is a neurodegenerative disease that is potentially reversible by shunt surgery in approximately 60% of patients. Imaging may provide a means to investigate brain tissue viability and oxygen metabolism in NPH patients. METHODS: Oxygen extraction fraction (OEF) mapping was generated from 3D multi-echo gradient echo MRI (mGRE) data using QQ-CCTV algorithm and cerebral blood flow (CBF) using 3D arterial spin labeling (ASL) MRI data, thereby calculating the cerebral metabolic rate of oxygen (CMRO2 = CBF × OEF × [H]a) in 16 NPH patients. Regression analyses using cortical gray matter and deep gray matter regions were conducted with age, gender, CSF stroke volume and normalized ventricular volume as independent variables. RESULTS: OEF showed significant negative correlations with normalized brain ventricular volumes in the whole brain (p = 0.004, q = 0.01), cortical gray matter (p = 0.004, q = 0.01), caudate (p = 0.02, q = 0.04), and pallidum (p = 0.03, q = 0.04), but no significant correlation with CSF stroke volume (q > 0.05). There was no significant finding with CBF or CMRO2. CONCLUSION: In NPH patients, low OEF in several regions was significantly correlated with large ventricular volumes, indicating decreased tissue oxygen metabolism with increased NPH severity. OEF mapping may provide a functional understanding of neurodegeneration in NPH and may improve monitoring of disease course and treatment outcomes.

Effects of sex and APOE ε4 genotype on brain mitochondrial high-energy phosphates in midlife individuals at risk for Alzheimer's disease: A 31Phosphorus MR spectroscopy study.

Age, female sex, and APOE epsilon 4 (APOE4) genotype are the three greatest risk factors for late-onset Alzheimer's disease (AD). The convergence of these risks creates a hypometabolic AD-risk profile unique to women, which may help explain their higher lifetime risk of AD. Less is known about APOE4 effects in men, although APOE4 positive men also experience an increased AD risk. This study uses 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to examine effects of sex and APOE4 status on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters (PME), phosphodiesters (PDE)] in 209 cognitively normal individuals at risk for AD, ages 40-65, 80% female, 46% APOE4 carriers (APOE4+). Women exhibited lower PCr/ATP and PCr/Pi levels than men in AD-vulnerable regions, including frontal, posterior cingulate, lateral and medial temporal cortex (multi-variable adjusted p≤0.037). The APOE4+ group exhibited lower PCr/ATP and PCr/Pi in frontal regions as compared to non-carriers (APOE4-) (multi-variable adjusted p≤0.005). Sex by APOE4 status interactions were observed in frontal regions (multi-variable adjusted p≤0.046), where both female groups and APOE4+ men exhibited lower PCr/ATP and PCr/Pi than APOE4- men. Among men, APOE4 homozygotes exhibited lower frontal PCr/ATP than heterozygotes and non-carriers. There were no significant effects of sex or APOE4 status on Pi/ATP and PME/PDE measures. Among midlife individuals at risk for AD, women exhibit lower PCr/ATP (e.g. higher ATP utilization) and lower PCr/Pi (e.g. higher energy demand) than age-controlled men, independent of APOE4 status. However, a double dose of APOE4 allele shifted men's brains to a similar metabolic range as women's brains. Examination of brain metabolic heterogeneity can support identification of AD-specific pathways within at-risk subgroups, further advancing both preventive and precision medicine for AD.

Silicone-based materials with tailored MR relaxation characteristics for use in reduced coil visibility and in tissue-mimicking phantom design.

BACKGROUND: The development of materials with tailored signal intensity in MR imaging is critically important both for the reduction of signal from non-tissue hardware, as well as for the construction of tissue-mimicking phantoms. Silicone-based phantoms are becoming more popular due to their structural stability, stretchability, longer shelf life, and ease of handling, as well as for their application in dynamic imaging of physiology in motion. Moreover, silicone can be also used for the design of stretchable receive radio-frequency (RF) coils. PURPOSE: Fabrication of materials with tailored signal intensity for MRI requires knowledge of precise T1 and T2 relaxation times of the materials used. In order to increase the range of possible relaxation times, silicone materials can be doped with gadolinium (Gd). In this work, we aim to systematically evaluate relaxation properties of Gd-doped silicone material at a broad range of Gd concentrations and at three clinically relevant magnetic field strengths (1.5 T, 3 T, and 7 T). We apply the findings for rendering silicone substrates of stretchable receive RF coils less visible in MRI. Moreover, we demonstrate early stage proof-of-concept applicability in tissue-mimicking phantom development. MATERIALS AND METHODS: Ten samples of pure and Gd-doped Ecoflex silicone polymer samples were prepared with various Gd volume ratios ranging from 1:5000 to 1:10, and studied using 1.5 T and 3 T clinical and 7 T preclinical scanners. T1 and T2 relaxation times of each sample were derived by fitting the data to Bloch signal intensity equations. A receive coil made from Gd-doped Ecoflex silicone polymer was fabricated and evaluated in vitro at 3 T. RESULTS: With the addition of a Gd-based contrast agent, it is possible to significantly change T2 relaxation times of Ecoflex silicone polymer (from 213 ms to 20 ms at 1.5 T; from 135 ms to 17 ms at 3 T; and from 111.4 ms to 17.2 ms at 7 T). T1 relaxation time is less affected by the introduction of the contrast agent (changes from 608 ms to 579 ms; from 802.5 ms to 713 ms at 3 T; from 1276 ms to 979 ms at 7 T). First results also indicate that liver, pancreas, and white matter tissues can potentially be closely mimicked using this phantom preparation technique. Gd-doping reduces the appearance of the silicone-based coil substrate during the MR scan by up to 81%. CONCLUSIONS: Gd-based contrast agents can be effectively used to create Ecoflex silicone polymer-based phantoms with tailored T2 relaxation properties. The relative low cost, ease of preparation, stretchability, mechanical stability, and long shelf life of Ecoflex silicone polymer all make it a good candidate for "MR invisible" coil development and bears promise for tissue-mimicking phantom development applicability.

Elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer's disease in midlife women.

Introduction: In preclinical studies, menopausal elevations in pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), trigger Alzheimer's disease (AD) pathology and synaptic loss in female animals. Herein, we took a translational approach to test whether gonadotropin elevations are linked to AD pathophysiology in women. Methods: We examined 191 women ages 40-65 years, carrying risk factors for late-onset AD, including 45 premenopausal, 67 perimenopausal, and 79 postmenopausal participants with clinical, laboratory, cognitive exams, and volumetric MRI scans. Half of the cohort completed 11C-Pittsburgh Compound B (PiB) amyloid-ß (Aß) PET scans. Associations between serum FSH, LH and biomarkers were examined using voxel-based analysis, overall and stratified by menopause status. Associations with region-of-interest (ROI) hippocampal volume, plasma estradiol levels, APOE-4 status, and cognition were assessed in sensitivity analyses. Results: FSH levels were positively associated with Aß load in frontal cortex (multivariable adjusted P≤0.05, corrected for family wise type error, FWE), an effect that was driven by the postmenopausal group (multivariable adjusted PFWE ≤ 0.044). LH levels were also associated with Aß load in frontal cortex, which did not survive multivariable adjustment. FSH and LH were negatively associated with gray matter volume (GMV) in frontal cortex, overall and in each menopausal group (multivariable adjusted PFWE ≤ 0.040), and FSH was marginally associated with ROI hippocampal volume (multivariable adjusted P = 0.058). Associations were independent of age, clinical confounders, menopause type, hormone therapy status, history of depression, APOE-4 status, and regional effects of estradiol. There were no significant associations with cognitive scores. Discussion: Increasing serum gonadotropin levels, especially FSH, are associated with higher Aß load and lower GMV in some AD-vulnerable regions of midlife women at risk for AD. These findings are consistent with preclinical work and provide exploratory hormonal targets for precision medicine strategies for AD risk reduction.

Femoral Head Vascularity After Arthroscopic Femoral Osteochondroplasty: An In Vivo Dynamic Contrast-Enhanced MRI Study.

Background: A serious concern with surgical procedures around the hip joint is iatrogenic injury of the arterial supply to the femoral head (FH) and consequent development of FH osteonecrosis. Cam-type morphology can extend to the posterosuperior area. Understanding the limit of the posterior superior extension of the femoral osteochondroplasty is paramount to avoid underresection and residual impingement while maintaining FH vascularity. Purpose/Hypothesis: The aim of this study was to quantify the impact of arthroscopic femoral osteochondroplasty on the FH vascular supply. It was hypothesized that keeping the superior extension of the resection zone anterior to the 12-o'clock position would maintain FH vascularity. Study Design: Case series; Level of evidence, 4. Methods: Ten adult patients undergoing arthroscopic femoroacetabular impingement (FAI) surgery were included in the study. Computed tomography (CT) scans were obtained before and after arthroscopic osteochondroplasty to define the extension of resection margins. To quantify FH vascularity, postoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was obtained at 2 time points: immediately after surgery and at the 3-month follow-up. Custom MRI analysis software was used to quantify perfusion. Results: CT scan analysis demonstrated that the superior resection margin was maintained anterior to the 12-o'clock position in half of the patients. The remining 5 patients had a mean posterior extension of 11.4° ± 7.5°. The immediate postoperative DCE-MRI revealed diminished venous outflow in the operative side but no difference in overall FH perfusion. At the 3-month follow-up DCE-MRI, there was no perfusion difference between the operative and nonoperative FHs. Conclusion: This study provides previously unreported quantitative MRI data on in vivo perfusion of the FH after the commonly performed arthroscopic femoral osteochondroplasty for the treatment of cam-type FAI. Maintaining resection margins anterior to the 12-o'clock position, or even 10° posteriorly, was not observed to impair perfusion to the FH.

Sex and menopause impact 31P-Magnetic Resonance Spectroscopy brain mitochondrial function in association with 11C-PiB PET amyloid-beta load.

Increasing evidence implicates sex and endocrine aging effects on brain bioenergetic aging in the greater lifetime risk of Alzheimer's disease (AD) in women. We conducted 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to assess the impact of sex and menopause on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters/phosphodiesters (PME/PDE)] in 216 midlife cognitively normal individuals at risk for AD, 80% female. Ninety-seven participants completed amyloid-beta (Aß) 11C-PiB PET. Women exhibited higher ATP utilization than men in AD-vulnerable frontal, posterior cingulate, fusiform, medial and lateral temporal regions (p < 0.001). This profile was evident in frontal cortex at the pre-menopausal and peri-menopausal stage and extended to the other regions at the post-menopausal stage (p = 0.001). Results were significant after multi-variable adjustment for age, APOE-4 status, midlife health indicators, history of hysterectomy/oophorectomy, use of menopause hormonal therapy, and total intracranial volume. While associations between ATP/PCr and Aß load were not significant, individuals with the highest Aß load were post-menopausal and peri-menopausal women with ATP/PCr ratios in the higher end of the distribution. No differences in Pi/PCr, Pi/ATP or PME/PDE were detected. Outcomes are consistent with dynamic bioenergetic brain adaptations that are associated with female sex and endocrine aging.

Ovarian steroid hormones: A long overlooked but critical contributor to brain aging and Alzheimer's disease.

Ovarian hormones, particularly 17ß-estradiol, are involved in numerous neurophysiological and neurochemical processes, including those subserving cognitive function. Estradiol plays a key role in the neurobiology of aging, in part due to extensive interconnectivity of the neural and endocrine system. This aspect of aging is fundamental for women's brains as all women experience a drop in circulating estradiol levels in midlife, after menopause. Given the importance of estradiol for brain function, it is not surprising that up to 80% of peri-menopausal and post-menopausal women report neurological symptoms including changes in thermoregulation (vasomotor symptoms), mood, sleep, and cognitive performance. Preclinical evidence for neuroprotective effects of 17ß-estradiol also indicate associations between menopause, cognitive aging, and Alzheimer's disease (AD), the most common cause of dementia affecting nearly twice more women than men. Brain imaging studies demonstrated that middle-aged women exhibit increased indicators of AD endophenotype as compared to men of the same age, with onset in perimenopause. Herein, we take a translational approach to illustrate the contribution of ovarian hormones in maintaining cognition in women, with evidence implicating menopause-related declines in 17ß-estradiol in cognitive aging and AD risk. We will review research focused on the role of endogenous and exogenous estrogen exposure as a key underlying mechanism to neuropathological aging in women, with a focus on whether brain structure, function and neurochemistry respond to hormone treatment. While still in development, this research area offers a new sex-based perspective on brain aging and risk of AD, while also highlighting an urgent need for better integration between neurology, psychiatry, and women's health practices.

Quantifying cerebrospinal fluid dynamics: A review of human neuroimaging contributions to CSF physiology and neurodegenerative disease.

Cerebrospinal fluid (CSF), predominantly produced in the ventricles and circulating throughout the brain and spinal cord, is a key protective mechanism of the central nervous system (CNS). Physical cushioning, nutrient delivery, metabolic waste, including protein clearance, are key functions of the CSF in humans. CSF volume and flow dynamics regulate intracranial pressure and are fundamental to diagnosing disorders including normal pressure hydrocephalus, intracranial hypotension, CSF leaks, and possibly Alzheimer's disease (AD). The ability of CSF to clear normal and pathological proteins, such as amyloid-beta (Aß), tau, alpha synuclein and others, implicates it production, circulation, and composition, in many neuropathologies. Several neuroimaging modalities have been developed to probe CSF fluid dynamics and better relate CSF volume and flow to anatomy and clinical conditions. Approaches include 2-photon microscopic techniques, MRI (tracer-based, gadolinium contrast, endogenous phase-contrast), and dynamic positron emission tomography (PET) using existing approved radiotracers. Here, we discuss CSF flow neuroimaging, from animal models to recent clinical-research advances, summarizing current endeavors to quantify and map CSF flow with implications towards pathophysiology, new biomarkers, and treatments of neurological diseases.

Vascularity of the early post-natal human distal femoral chondroepiphysis: Quantitative MRI analysis.

Purpose: Injury to or abnormality of developing distal femoral chondroepiphysis blood supply has been implicated in osteochondritis dissecans development. Progressive decrease in epiphyseal cartilage blood supply occurs in normal development; however, based on animal studies, it is hypothesized that there is greater decrease in regions more prone to osteochondritis dissecans lesions. We aimed to quantify differential regional perfusion of the immature distal femoral chondroepiphysis. We hypothesized there is decreased perfusion in the lateral aspect of the medial femoral condyle, the classic osteochondritis dissecans lesion location. Methods: Five fresh-frozen human cadaveric knees (0-6 months old) were utilized. The superficial femoral artery was cannulated proximally and contrast-enhanced magnetic resonance imaging performed using a previously reported protocol for quantifying osseous and soft tissue perfusion. Regions of interest were defined, and signal enhancement changes between pre- and post-contrast images, normalized to background muscle, were compared. Results: When comparing average normalized post-contrast signal enhancement of whole condyles, as well as distal, posterior, and inner (toward the notch) aspects of the medial and lateral condyles, no significant perfusion differences between condyles were found. In the medial condyle, no significant perfusion difference was found between the medial and lateral aspects. Conclusion: We quantified immature distal femoral chondroepiphysis regional vascularity in the early post-natal knee. In specimens aged 0-6 months, no distinct watershed region was detected. Despite possible limitations, given small sample size, as well as resolution of magnetic resonance imaging and analysis, our results suggest the hypothesized vascular abnormality predisposing osteochondritis dissecans either does not occur universally or occurs after this developmental age.

Differential regional perfusion of the human anterior cruciate ligament: quantitative magnetic resonance imaging assessment.

PURPOSE: Surgical reconstruction is the current standard for ACL rupture treatment in active individuals. Recently, there is renewed interest in primary repair of proximal ACL tears. Despite this, ACL biology and healing potential are currently not well understood. Vascularity is paramount in ACL healing; however, previous ACL vascularity studies have been limited to qualitative histological and dissection-based techniques. The study objective was to use contrast-enhanced quantitative-MRI to compare relative perfusion of proximal, middle, and distal thirds of the in situ ACL. We hypothesized perfusion would be greatest in the proximal third. METHODS: Fourteen cadaveric knees were studied (8 females, 6 males), age 25-61 years. Superficial femoral, anterior tibial, and posterior tibial arteries were cannulated; without intraarticular dissection. Contrast-enhanced quantitative-MRI was performed using a previously established protocol. ACL regions corresponding to proximal, middle, and distal thirds were identified on sagittal-oblique pre-contrast images. Signal enhancement (normalized to tibial plateau cartilage) was quantified to represent regional perfusion as a percentage of total ACL perfusion. Comparative statistics were computed using repeated measures ANOVA, and pairwise comparisons performed using the Bonferroni method. RESULTS: Relative perfusion to proximal, middle, and distal ACL zones were 56.0% ±17.4%, 28.2% ±14.6%, and 15.8% ±16.3%, respectively (p = 0.002). Relative perfusion to the proximal third was significantly greater than middle (p = 0.007) and distal (p = 0.001). No statistically relevant difference in relative perfusion was found to middle and distal thirds (p = 0.281). Post-hoc subgroup analysis demonstrated greater proximal perfusion in males (66.9% ± 17.3%) than females (47.8% ± 13.0%), p = 0.036. CONCLUSION: Using quantitative-MRI, in situ adult ACL demonstrated greatest relative perfusion to the proximal third, nearly 2 times greater than the middle third and 3 times greater than the distal third. Knowledge of differential ACL vascular supply is important for understanding pathogenesis of ACL injury and the process of biological healing following various forms of surgical treatment.

Use of small animal PET-CT imaging for in vivo assessment of tendon-to-bone healing: A pilot study.

BACKGROUND: The availability of non-invasive means to evaluate and monitor tendon-bone healing processes in-vivo is limited. Micro Positron-Emission-Tomography (µPET) using 18F-Fluoride is a minimally invasive imaging modality, with which osteoblast activity and bone turnover can be assessed. The aim of this study was to investigate the use of serial in-vivo µPET/CT scans to evaluate bone turnover along the graft-tunnel interface in a rat ACL (anterior cruciate ligament) reconstruction model. METHODS: Unilateral autograft ACL reconstruction was performed in six rats. µPET/CT-scans using 18F-Fluoride were performed 7, 14, 21, and 28 days postoperatively. Standard uptake values (SUV) were calculated for three tunnel regions (intraarticular aperture (IAA), mid-tunnel, and extraarticular aperture (EAA)) of the proximal tibia. Animals were sacrificed at 28 days and evaluated with µCT and histological analysis. RESULTS: SUVs in both bone tunnels showed an increased 18F-Fluoride uptake at 7 days when compared to 14, 21, and 28 days. SUVs showed a gradient on the tibial side, with most bone turnover in the IAA and least in the EAA. At 7, 14, 21, and 28 days, there were significantly higher SUV values in the IAA compared to the EAA (p = .01, < .01, < .01, < .01). SUVs positively correlated with new bone volumetric density obtained with µCT (r = 0.449, p = .013). Volumetric density of newly formed bone detected on µCT correlated with osteoblast numbers observed along the tunnels in histological sections (r = 0.452, p < .016). CONCLUSIONS: Serial in-vivo µPET/CT-scanning has the potential to provide insight into bone turnover and therefore osteoblastic activity during the healing process. As a result, it allows us to directly measure the effect of interventional strategies in tendon-bone healing.

Tau PET following acute TBI: Off-target binding to blood products, tauopathy, or both?

Repeated mild Traumatic Brain Injury (TBI) is a risk factor for Chronic Traumatic Encephalopathy (CTE), characterized pathologically by neurofibrillary tau deposition in the depths of brain sulci and surrounding blood vessels. The mechanism by which TBI leads to CTE remains unknown but has been posited to relate to axonal shear injury leading to release and possibly deposition of tau at the time of injury. As part of an IRB-approved study designed to learn how processes occurring acutely after TBI may predict later proteinopathy and neurodegeneration, we performed tau PET using 18F-MK6240 and MRI within 14 days of complicated mild TBI in three subjects. PET radiotracer accumulation was apparent in regions of traumatic hemorrhage in all subjects, with prominent intraparenchymal PET signal in one young subject with a history of repeated sports-related concussions. These results are consistent with off-target tracer binding to blood products as well as possible on-target binding to chronically and/or acutely-deposited neurofibrillary tau. Both explanations are highly relevant to applying tau PET to understanding TBI and CTE. Additional study is needed to assess the potential utility of tau PET in understanding how processes occurring acutely after TBI, such as release and deposition of tau and blood from damaged axons and blood vessels, may relate to development CTE years later.

Association of Reproductive History With Brain MRI Biomarkers of Dementia Risk in Midlife.

BACKGROUND AND OBJECTIVES: To examine associations between indicators of estrogen exposure from women's reproductive history and brain MRI biomarkers of Alzheimer disease (AD) in midlife. METHODS: We evaluated 99 cognitively normal women 52 ± 6 years of age and 29 men 52 ± 7 years of age with reproductive history data, neuropsychological testing, and volumetric MRI scans. We used multiple regressions to examine associations among reproductive history indicators, voxel-wise gray matter volume (GMV), and memory and global cognition scores, adjusting for demographics and midlife health indicators. Exposure variables were menopause status, age at menarche, age at menopause, reproductive span, hysterectomy status, number of children and pregnancies, and use of menopause hormonal therapy (HT) and hormonal contraceptives (HC). RESULTS: All menopausal groups exhibited lower GMV in AD-vulnerable regions compared to men, with perimenopausal and postmenopausal groups also exhibiting lower GMV in temporal cortex compared to the premenopausal group. Reproductive span, number of children and pregnancies, and use of HT and HC were positively associated with GMV, chiefly in temporal cortex, frontal cortex, and precuneus, independent of age, APOE ε4 status, and midlife health indicators. Although reproductive history indicators were not directly associated with cognitive measures, GMV in temporal regions was positively associated with memory and global cognition scores. DISCUSSION: Reproductive history events signaling more estrogen exposure such as premenopausal status, longer reproductive span, higher number of children, and use of HT and HC were associated with larger GMV in women in midlife. Further studies are needed to elucidate sex-specific biological pathways through which reproductive history influences cognitive aging and AD risk.