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.

Bidirectional electromagnetic control of the hypothalamus regulates feeding and metabolism.

Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP-TRPV1). Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase-Cre mice, which express Cre in glucose-sensing neurons. Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types.

Is it time to switch your T1W sequence? Assessing the impact of prospective motion correction on the reliability and quality of structural imaging.

New large neuroimaging studies, such as the Adolescent Brain Cognitive Development study (ABCD) and Human Connectome Project (HCP) Development studies are adopting a new T1-weighted imaging sequence with prospective motion correction (PMC) in favor of the more traditional 3-Dimensional Magnetization-Prepared Rapid Gradient-Echo Imaging (MPRAGE) sequence. Here, we used a developmental dataset (ages 5-21, N = 348) from the Healthy Brain Network (HBN) Initiative to directly compare two widely used MRI structural sequences: one based on the Human Connectome Project (MPRAGE) and another based on the ABCD study (MPRAGE+PMC). We aimed to determine if the morphometric measurements obtained from both protocols are equivalent or if one sequence has a clear advantage over the other. The sequences were also compared through quality control measurements. Inter- and intra-sequence reliability were assessed with another set of participants (N = 71) from HBN that performed two MPRAGE and two MPRAGE+PMC sequences within the same imaging session, with one MPRAGE (MPRAGE1) and MPRAGE+PMC (MPRAGE+PMC1) pair at the beginning of the session and another pair (MPRAGE2 and MPRAGE+PMC2) at the end of the session. Intraclass correlation coefficients (ICC) scores for morphometric measurements such as volume and cortical thickness showed that intra-sequence reliability is the highest with the two MPRAGE+PMC sequences and lowest with the two MPRAGE sequences. Regarding inter-sequence reliability, ICC scores were higher for the MPRAGE1 - MPRAGE+PMC1 pair at the beginning of the session than the MPRAGE1 - MPRAGE2 pair, possibly due to the higher motion artifacts in the MPRAGE2 run. Results also indicated that the MPRAGE+PMC sequence is robust, but not impervious, to high head motion. For quality control metrics, the traditional MPRAGE yielded better results than MPRAGE+PMC in 5 of the 8 measurements. In conclusion, morphometric measurements evaluated here showed high inter-sequence reliability between the MPRAGE and MPRAGE+PMC sequences, especially in images with low head motion. We suggest that studies targeting hyperkinetic populations use the MPRAGE+PMC sequence, given its robustness to head motion and higher reliability scores. However, neuroimaging researchers studying non-hyperkinetic participants can choose either MPRAGE or MPRAGE+PMC sequences, but should carefully consider the apparent tradeoff between relatively increased reliability, but reduced quality control metrics when using the MPRAGE+PMC sequence.

Study of Intraventricular Cerliponase Alfa for CLN2 Disease.

BACKGROUND: Recombinant human tripeptidyl peptidase 1 (cerliponase alfa) is an enzyme-replacement therapy that has been developed to treat neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a rare lysosomal disorder that causes progressive dementia in children. METHODS: In a multicenter, open-label study, we evaluated the effect of intraventricular infusion of cerliponase alfa every 2 weeks in children with CLN2 disease who were between the ages of 3 and 16 years. Treatment was initiated at a dose of 30 mg, 100 mg, or 300 mg; all the patients then received the 300-mg dose for at least 96 weeks. The primary outcome was the time until a 2-point decline in the score on the motor and language domains of the CLN2 Clinical Rating Scale (which ranges from 0 to 6, with 0 representing no function and 3 representing normal function in each of the two domains), which was compared with the time until a 2-point decline in 42 historical controls. We also compared the rate of decline in the motor-language score between the two groups, using data from baseline to the last assessment with a score of more than 0, divided by the length of follow-up (in units of 48 weeks). RESULTS: Twenty-four patients were enrolled, 23 of whom constituted the efficacy population. The median time until a 2-point decline in the motor-language score was not reached for treated patients and was 345 days for historical controls. The mean (±SD) unadjusted rate of decline in the motor-language score per 48-week period was 0.27±0.35 points in treated patients and 2.12±0.98 points in 42 historical controls (mean difference, 1.85; P<0.001). Common adverse events included convulsions, pyrexia, vomiting, hypersensitivity reactions, and failure of the intraventricular device. In 2 patients, infections developed in the intraventricular device that was used to administer the infusion, which required antibiotic treatment and device replacement. CONCLUSIONS: Intraventricular infusion of cerliponase alfa in patients with CLN2 disease resulted in less decline in motor and language function than that in historical controls. Serious adverse events included failure of the intraventricular device and device-related infections. (Funded by BioMarin Pharmaceutical and others; CLN2 ClinicalTrials.gov numbers, NCT01907087 and NCT02485899 .).

In Vivo Dentate Nucleus Gamma-aminobutyric Acid Concentration in Essential Tremor vs. Controls.

Despite its high prevalence, essential tremor (ET) is among the most poorly understood neurological diseases. The presence and extent of Purkinje cell (PC) loss in ET is the subject of controversy. PCs are a major storehouse of central nervous system gamma-aminobutyric acid (GABA), releasing GABA at the level of the dentate nucleus. It is therefore conceivable that cerebellar dentate nucleus GABA concentration could be an in vivo marker of PC number. We used in vivo 1H magnetic resonance spectroscopy (MRS) to quantify GABA concentrations in two cerebellar volumes of interest, left and right, which included the dentate nucleus, comparing 45 ET cases to 35 age-matched controls. 1H MRS was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in two cerebellar volumes of interest (left and right) that included the dentate nucleus. The two groups did not differ with respect to our primary outcome of GABA concentration (given in institutional units). For the right dentate nucleus, [GABA] in ET cases = 2.01 ± 0.45 and [GABA] in controls = 1.86 ± 0.53, p = 0.17. For the left dentate nucleus, [GABA] in ET cases = 1.68 ± 0.49 and [GABA] controls = 1.80 ± 0.53, p = 0.33. The controls had similar dentate nucleus [GABA] in the right vs. left dentate nucleus (p = 0.52); however, in ET cases, the value on the right was considerably higher than that on the left (p = 0.001). We did not detect a reduction in dentate nucleus GABA concentration in ET cases vs. CONTROLS: One interpretation of the finding is that it does not support the existence of PC loss in ET; however, an alternative interpretation is the observed pattern could be due to the effects of terminal sprouting in ET (i.e., collateral sprouting from surviving PCs making up for the loss of GABA-ergic terminals from PC degeneration). Further research is needed.

High-resolution rapid neonatal whole-body composition using 3.0 Tesla chemical shift magnetic resonance imaging.

BackgroundTo evaluate a whole-body rapid imaging technique to calculate neonatal lean body mass and percentage adiposity using 3.0 Tesla chemical shift magnetic resonance imaging (MRI).MethodsA 2-Point Dixon MRI technique was used to calculate whole-body fat and water images in term (n=10) and preterm (n=15) infants.ResultsChemical shift images were obtained in 42 s. MRI calculated whole-body mass correlated closely with measured body weight (R2=0.87; P<0.001). Scan-rescan analysis demonstrated a 95% limit of agreement of 1.3% adiposity. Preterm infants were born at a median of 25.7 weeks' gestation with birth weight 840 g. At term-corrected age, former preterm infants were lighter than term-born controls, 2,519 vs. 3,094 g regressing out age and group as covariates (P=0.005). However, this was not because of reduced percentage adiposity 26% vs. 24% (P=0.28). At term-corrected age, former preterm infants had significantly reduced lean body mass compared with that of term-born controls 1,935 vs. 2,416 g (P=0.002).ConclusionRapid whole-body imaging for assessment of lean body mass and adiposity in term and preterm infants is feasible, accurate, and repeatable. Deficits in whole-body mass in former preterm infants at term-corrected age are due to reductions in lean body mass not due to differences in adiposity.

Diagnostic accuracy of intracellular uptake rates calculated using dynamic Gd-EOB-DTPA-enhanced MRI for hepatic fibrosis stage.

PURPOSE: To assess the diagnostic accuracy of intracellular uptake rates (Ki ), and other quantitative pharmacokinetic (PK) parameters, for hepatic fibrosis stage; to compare this accuracy with a previously published semiquantitative metric, contrast enhancement index (CEI); and to assess variability of these parameters between liver regions. MATERIALS AND METHODS: This was a case-control study design. Dynamic Gd-EOB-DTPA-enhanced 1.5T magnetic resonance imaging (MRI) was performed prospectively in 22 subjects with varying known stages of hepatic fibrosis. PK parameters and CEI were derived from the whole livers and from three fixed regions of interest (ROIs) in all subjects. Spearman rank correlation coefficients were computed to assess the relationship between fibrosis stages and each parameter. Receiver operating characteristic (ROC) curves were constructed to discriminate severe fibrosis (stages 3-4) from nonsevere fibrosis (stages 0-2). The coefficient of variation (CV) was calculated to assess variability in parameters between ROIs. RESULTS: Ki and fibrosis stage were significantly correlated (R = -0.55, 95% confidence interval [CI] [-0.79, -0.14], P = 0.01). Area under ROC curve (AUC) in distinguishing severe from nonsevere fibrosis for Ki was 0.84 (95% CI [0.65,1.00]), and for CEI was 0.64 (95% CI [0.39, 0.89]) (P = 0.0248). CV for Ki and CEI were 33.4 and 5.8, respectively. The only other parameter in the PK model having significant correlation with fibrosis stage was absolute arterial blood flow (Fa ) (R = -0.48, 95% CI [-0.75,-0.05], P = 0.03). CONCLUSION: Hepatocyte intracellular uptake rate, Ki , derived from dynamic contrast-enhanced MRI, correlates with fibrosis stage and may contribute to a noninvasive biomarker of hepatic fibrosis. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:1177-1185.

Contribution of Circulatory Disturbances in Subchondral Bone to the Pathophysiology of Osteoarthritis.

PURPOSE OF REVIEW: This review describes the contributions of abnormal bone circulation to the pathophysiology of osteoarthritis. Combining dynamic imaging with MRI and PET with previous observations reveals that venous stasis and a venous outlet syndrome is most likely the key circulatory pathology associated with the initiation or progression of osteoarthritis. RECENT FINDINGS: MRI and PET have revealed that venous outflow obstruction results in physicochemical changes in subchondral bone to which osteoblasts are responsive. The osteoblasts express an altered pattern of cytokines, many of which can serve as structural or signaling molecules contributing to both bone remodeling and cartilage degeneration. The patterns of circulatory changes are associated with alterations in the physicochemical environment of subchondral bone, including hypoxia. Osteoblast cytokines can transit the subchondral bone plate and calcified cartilage and communicate with chondrocytes.

Focal osteonecrosis in the femoral head following stable anatomic fixation of displaced femoral neck fractures.

INTRODUCTION: Femoral head (FH) osteonecrosis (ON) and subsequent segmental collapse is a major concern following displaced femoral neck fractures (FNF). We aimed to quantify residual perfusion to the FH following FNF and evaluate the viability of the FH overtime after surgical fixation. MATERIALS AND METHODS: Twenty-three patients with FNF underwent dynamic contrast-enhanced (DCE)-MRI to estimate bone perfusion in the FH, using the contralateral side as control. Following open anatomic reduction and a length/angle-stable fixation, a special MRI sequence evaluated the FH for ON changes over time at 3 and 12 months after surgery. RESULTS: We found significant compromise of both arterial inflow [83.1%-initial area under the curve (IAUC) and 73.8%-peak) and venous outflow (243.2%-elimination rate (K el)] in the FH of the fractured side. The supero-medial quadrant suffered the greatest decrease in arterial inflow with a significant decrease of 71.6% (IAUC) and 68.5% (peak). Post-operative MRI revealed a high rate (87%-20/23) of small ON segments within the FH, and all developed in the anterior aspect of the supero-medial quadrants. Fracture characteristics, including subcapital FNF, varus deformity, posterior roll-off ≥20° and Pauwel's angle of 30°-50° demonstrated a greater decrease in perfusion compared to contralateral controls. CONCLUSION: FNF significantly impaired the vascular supply to the FH, resulting in high incidence of small ON segments in the supero-medial quadrant of the FH. However, maintained perfusion, probably through the inferior retinacular system, coupled with urgent open anatomic reduction and stable fixation resulted in excellent clinical and radiographic outcomes despite a high rate of small ON segments noted on MRI. LEVEL OF EVIDENCE: Level I: Prognostic Investigation.

The Impact of Emotional States on Cognitive Control Circuitry and Function.

Typically in the laboratory, cognitive and emotional processes are studied separately or as a stream of fleeting emotional stimuli embedded within a cognitive task. Yet in life, thoughts and actions often occur in more lasting emotional states of arousal. The current study examines the impact of emotions on actions using a novel behavioral paradigm and functional neuroimaging to assess cognitive control under sustained states of threat (anticipation of an aversive noise) and excitement (anticipation of winning money). Thirty-eight healthy adult participants were scanned while performing an emotional go/no-go task with positive (happy faces), negative (fearful faces), and neutral (calm faces) emotional cues, under threat or excitement. Cognitive control performance was enhanced during the excited state relative to a nonarousing control condition. This enhanced performance was paralleled by heightened activity of frontoparietal and frontostriatal circuitry. In contrast, under persistent threat, cognitive control was diminished when the valence of the emotional cue conflicted with the emotional state. Successful task performance in this conflicting emotional condition was associated with increased activity in the posterior cingulate cortex, a default mode network region implicated in complex processes such as processing emotions in the context of self and monitoring performance. This region showed positive coupling with frontoparietal circuitry implicated in cognitive control, providing support for a role of the posterior cingulate cortex in mobilizing cognitive resources to improve performance. These findings suggest that emotional states of arousal differentially modulate cognitive control and point to the potential utility of this paradigm for understanding effects of situational and pathological states of arousal on behavior.

Brain γ-aminobutyric acid (GABA) detection in vivo with the J-editing (1) H MRS technique: a comprehensive methodological evaluation of sensitivity enhancement, macromolecule contamination and test-retest reliability.

Abnormalities in brain γ-aminobutyric acid (GABA) have been implicated in various neuropsychiatric and neurological disorders. However, in vivo GABA detection by (1) H MRS presents significant challenges arising from the low brain concentration, overlap by much stronger resonances and contamination by mobile macromolecule (MM) signals. This study addresses these impediments to reliable brain GABA detection with the J-editing difference technique on a 3-T MR system in healthy human subjects by: (i) assessing the sensitivity gains attainable with an eight-channel phased-array head coil; (ii) determining the magnitude and anatomic variation of the contamination of GABA by MM; and (iii) estimating the test-retest reliability of the measurement of GABA with this method. Sensitivity gains and test-retest reliability were examined in the dorsolateral prefrontal cortex (DLPFC), whereas MM levels were compared across three cortical regions: DLPFC, the medial prefrontal cortex (MPFC) and the occipital cortex (OCC). A three-fold higher GABA detection sensitivity was attained with the eight-channel head coil compared with the standard single-channel head coil in DLPFC. Despite significant anatomical variation in GABA + MM and MM across the three brain regions (p < 0.05), the contribution of MM to GABA + MM was relatively stable across the three voxels, ranging from 41% to 49%, a non-significant regional variation (p = 0.58). The test-retest reliability of GABA measurement, expressed as either the ratio to voxel tissue water (W) or to total creatine, was found to be very high for both the single-channel coil and the eight-channel phased-array coil. For the eight-channel coil, for example, Pearson's correlation coefficient of test vs. retest for GABA/W was 0.98 (R(2) = 0.96, p = 0.0007), the percentage coefficient of variation (CV) was 1.25% and the intraclass correlation coefficient (ICC) was 0.98. Similar reliability was also found for the co-edited resonance of combined glutamate and glutamine (Glx) for both coils. Copyright © 2016 John Wiley & Sons, Ltd.

Comparison of the upper airway dynamics of oronasal and nasal masks with positive airway pressure treatment using cine magnetic resonance imaging.

PURPOSE: It is known that oronasal masks are not as effective at opening the upper airway compared to nasal only continuous positive airway pressure (CPAP) masks in patients with sleep-disordered breathing. However, the physiological mechanism for this difference in efficacy is not known; although, it has been hypothesized to involve the retroglossal and/or retropalatal region of the upper airway. The objective of this study was to investigate differences in retroglossal and retropalatal anterior-posterior space with the use of oronasal vs. nasal CPAP masks using real-time cine magnetic resonance imaging (cMRI). METHODS: Ten subjects (eight men, two women) with obstructive sleep apnea (OSA) were given cMRI with both nasal and oronasal CPAP masks. Each subject was imaged with each interface at pressures of 5, 10, and 15 cm of H2O, while in the supine position along the sagittal plane. RESULTS: The oronasal mask produced significantly less airway opening in the retropalatal region of the upper airway compared to the nasal mask interface. During exhalation, mask style had a significant effect on anterior-posterior distance p = 0.016. No differences were found in the retroglossal region between mask styles. CONCLUSIONS: Our study confirmed previous findings showing differences in treatment efficacy between oronasal and nasal mask styles. We have shown anatomic evidence that the nasal mask is more effective in opening the upper airway compared to the oronasal mask in the retropalatal region.

Quantitative assessment of patellar vascularity following bone-patellar tendon-bone autograft harvest for ACL reconstruction.

PURPOSE: Recent anatomic studies have suggested that the dominant arterial supply of the patella enters through the inferior pole. Based upon these findings, we hypothesized that bone-patellar tendon-bone graft harvest can significantly diminish patellar vascularity. METHODS: Nine matched pair cadaveric knee specimens (mean age 47.4 years) were dissected and cannulated. A single knee was selected to undergo routine graft harvest, and the contralateral knee was left intact to serve as a control. Gadolinium was injected, and magnetic resonance imaging (MRI) signal enhancement was quantified to determine differences in uptake. Each matched pair was subsequently injected with a urethane polymer compound and dissected to correlate vessel disruption with MRI findings. RESULTS: We identified two predominating patterns of vessel entry. In one pattern, the vessel entered the inferomedial aspect (five o'clock/right, seven o'clock/left) of the patella and was disrupted by graft harvest in 2/9 (22.2 %) pairs. In the second pattern, the vessel entered further medial (four o'clock/right, eight o'clock/left) and was not disrupted (7/9, 78.8 %). The mean decrease in gadolinium uptake following disruption of the predominant vessel measured 56.2 % (range 42.6-69.5 %) compared to an average decrease of 18.3 % (range 7.1-29.1 %) when the dominant arterial supply to the inferior pole remained intact (p < 0.04). CONCLUSION: Medial entry of the predominant vessel precluded vessel disruption. Disruption of the dominant arterial supply can result in a significant decrease in patellar vascularity. Modification of graft harvest techniques and areas of surgical dissection should be explored to minimize vascular insult. Further correlation with clinical studies/outcomes is necessary to determine a potential association between vascular insult and anterior knee pain.

Transgenic mice overexpressing amyloid precursor protein exhibit early metabolic deficits and a pathologically low leptin state associated with hypothalamic dysfunction in arcuate neuropeptide Y neurons.

Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-ß (Aß) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated with Aß. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excess Aß can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aß accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aß.

Reproducibility and effect of tissue composition on cerebellar γ-aminobutyric acid (GABA) MRS in an elderly population.

MRS provides a valuable tool for the non-invasive detection of brain γ-aminobutyric acid (GABA) in vivo. GABAergic dysfunction has been observed in the aging cerebellum. The study of cerebellar GABA changes is of considerable interest in understanding certain age-related motor disorders. However, little is known about the reproducibility of GABA MRS in an aged population. Therefore, this study aimed to explore the feasibility and reproducibility of GABA MRS in the aged cerebellum at 3.0 T and to examine the effect of differing tissue composition on GABA measurements. MRI and (1)H MRS examinations were performed on 10 healthy elderly volunteers (mean age, 75.2 ± 6.5 years) using a 3.0-T Siemens Tim Trio scanner. Among them, five subjects were scanned twice to assess the short-term reproducibility. The MEGA-PRESS (Mescher-Garwood point-resolved spectroscopy) J-editing sequence was used for GABA detection in two volumes of interest (VOIs) in the left and right cerebellar dentate. MRS data processing and quantification were performed with LCModel 6.3-0L using two separate basis sets, generated from density matrix simulations using published values for chemical shifts and J couplings. Raw metabolite levels from LCModel outputs were corrected for cerebrospinal fluid contamination and relaxation. GABA-edited spectra yielded robust and stable GABA measurements with averaged intra-individual coefficients of variation for corrected GABA+ between 4.0 ± 2.8% and 13.4 ± 6.3%, and inter-individual coefficients of variation between 12.6% and 24.2%. In addition, there was a significant correlation between GABA+ obtained with the two LCModel basis sets. Overall, our results demonstrated the feasibility and reproducibility of cerebellar GABA-edited MRS at 3.0 T in an elderly population. This information might be helpful for studies using this technique to study GABA changes in normal or diseased aging brain, e.g. for power calculations and the interpretation of longitudinal observations.

Regional analysis of femoral head perfusion following displaced fractures of the femoral neck.

PURPOSE: To assess regional variations in the arterial and venous blood supply to the femoral head following displaced fracture of the femoral neck using dynamic contrast enhanced (DCE)-MRI quadrant analysis. MATERIALS AND METHODS: A total of 27 subjects with displaced femoral neck fractures were enrolled in the study. Quadrant specific DCE-MRI perfusion analysis was performed on a 1.5 Tesla MRI scanner. Simultaneous imaging of control and displaced fractured hips was done for comparison. RESULTS: Quadrant specific decreases were found in the arterial (A (0.52 versus 0.27; P = 5.7E-13), Akep (1.0/min(-1) versus 0.41/min(-1) ; P = 1.3E-9) and venous (kel (0.05/min(-1) versus -0.02/min(-1) ; P = 5.1E-5) supply to the femoral head between control and injured sides using a two-factor analysis of variance test. The fractional perfusion (initial area under the curve) in the supero/inferolateral quadrants was 49% min/54% min, in the supero/inferomedial quadrants was 43% min/46% min and for the total femoral head was 39% min on the fracture versus control sides. CONCLUSION: Quadrant specific decreases in arterial and venous perfusion on the fracture side were observed when compared with control.

The effect of antegrade femoral nailing on femoral head perfusion: a comparison of piriformis fossa and trochanteric entry points.

INTRODUCTION: Piriformis fossa entry antegrade femoral nailing is a common method for stabilizing diaphyseal femur fractures. However, clinically significant complications such as chronic hip pain, hip abductor weakness, heterotopic ossification and femoral head osteonecrosis have been reported. A recent cadaveric study found that piriformis entry nailing damaged either the deep branch of the medial femoral circumflex artery (MFCA) or its distal superior retinacular artery branches in 100% of specimens and therefore recommended against its use. However, no study has quantitatively assessed the effect of different femoral entry points on femoral head perfusion. MATERIALS AND METHODS: Twelve fresh-frozen cadaveric lower extremity specimens were randomly allocated to either piriformis fossa or trochanteric entry nailing using a 13-mm reamer. The contralateral hip served as an internal matched control. All specimens subsequently underwent gadolinium-enhanced fat-suppressed gradient-echo sequence MRI to assess femoral head perfusion. Gross dissection was also performed to assess MFCA integrity and distance to the opening reamer path. RESULTS: MRI quantification analysis revealed near full femoral head perfusion with no significant difference between the piriformis and trochanteric starting points (95 vs. 97%, p = 0.94). There was no observed damage to the deep MFCA in either group. The mean distance from the reamer path to the deep MFCA was 3.2 mm in the piriformis group compared to 18.5 mm in the trochanteric group (p = 0.001). Additionally, there was a significantly greater number of mean terminal superior retinacular vessels damaged by the opening reamer in the piriformis cohort (1 vs. 0; p = 0.007). CONCLUSIONS: No statistically significant difference in femoral head perfusion was found between the two groups. Therefore, we cannot recommend against the use of piriformis entry femoral nails. However, we caution against multiple errant starting point attempts and recommend meticulous soft tissue protection during the procedure.

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.