[Expert consensus on clinical drug prevention and treatment of osteonecrosis of the femoral head(2022)].

With the in-depth understanding of osteonecrosis of femoral head (ONFH), and more and more patients seeking medical treatment in the early stage of the disease, surgical treatment of femoral head necrosis alone is no longer sufficient for the current treatment of patients' demand, how to rationally and effectively apply drugs to strengthen the early prevention and treatment of femoral head necrosis and delay the progression of disease is becoming more and more important. This article combines the latest expert consensus and evidence-based medical evidence on the principles of ONFH diagnosis and treatment in Chinese and Western medicine at home and abroad, combined with domestic actual clinical application experience, and is organized by experts from Association Related to Circulation Osseous Chinese Microcirculation Society (CSM-ARCO) to write this consensus, focusing on the types of ONFH drugs, the characteristics, safety, rationality and basic principles of drug use provide reference opinions for the safe, reasonable, standardized and effective drug use of medical institutions at all levels. This consensus is only an expert guideline based on literature and clinical experience, not as a requirement for mandatory implementation, let alone as a legal basis. The clinical practice could be tailored to the actual local conditions to develop appropriate prevention and treatment measures for patients.

Activatable fluorescent probes for imaging and diagnosis of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that is primarily manifested as synovitis and polyarticular opacity and typically leads to serious joint damage and irreversible disability, thus adversely affecting locomotion ability and life quality. Consequently, good prognosis heavily relies on the early diagnosis and effective therapeutic monitoring of RA. Activatable fluorescent probes play vital roles in the detection and imaging of biomarkers for disease diagnosis and in vivo imaging. Herein, we review the fluorescent probes developed for the detection and imaging of RA biomarkers, namely reactive oxygen/nitrogen species (hypochlorous acid, peroxynitrite, hydroxyl radical, nitroxyl), pH, and cysteine, and address the related challenges and prospects to inspire the design of novel fluorescent probes and the improvement of their performance in RA studies.

Reliability and Repeatability of the China-Japan Friendship Hospital Typing Classification for Nontraumatic Osteonecrosis of the Femoral Head.

BACKGROUND: The purpose of this study was to analyze the interobserver reliability and intraobserver repeatability of the China-Japan Friendship Hospital (CJFH) typing classification system for nontraumatic osteonecrosis of the femoral head (ONFH). METHODS: Image data of 50 hips were randomly selected in 289 patients (433 hips) with ONFH who underwent treatment in the China-Japan Friendship Hospital from 2012 to 2016. Bilateral hip plain radiography, magnetic resonance imaging (MRI), or computerized tomography (CT) were performed in all hips. The assessments were performed by 8 new residents independently, and the repeatability was assessed at 4-week intervals. Evaluation indicators included the size, location, and extent of necrotic lesions. Kappa values were used to determine the reliability and repeatability. RESULTS: According to the CJFH classification system, 2,800 evaluations were performed with an average interobserver Kappa value of 0.711, and 400 assessments were performed with an average intraobserver Kappa value of 0.748. Reliability analysis indicated a higher reliability and repeatability of this classification system. Critical factors affecting the consistency included the accurate selection of the median coronal plane and definitive tri-pillar division of the femoral head. CONCLUSION: The CJFH classification system is a simple and direct evaluation model for ONFH with substantial inter- and intraobserver reliability.

[Focused extracorporeal shock wave therapy with centrifugal exercise for the treatment of greater trochanteric pain syndrome].

OBJECTIVE: To explore the clinical efficacy of focused extracorporeal shock wave therapy with centrifugal exercise in the treatment of greater trochanteric pain syndrome. METHODS: From September 2017 to June 2019, 53 eligible cases of greater trochanteric pain syndrome were randomly divided into observation group (29 cases) and control group (24 cases). In observation group, there were 8 males and 21 females, aged from 38 to 62 years old with an average of (49.96±6.39) years old; the course of disease ranged from 6 to 13 months with an average of (8.58±1.99) months;treated with focused extracorporeal shock wave therapy with centrifugal exercise. In control group, there were 5 males and 19 females, aged from 39 to 62 years old with an average of (52.79±5.86) years old;the course of disease ranged from 6 to 14 months with an average of (9.04±2.51) months;treated with centrifugal exercise alone. Visual analogue scale (VAS) and hip Harris score were measured before ESWT treatment and at 1, 2, and 6 months to evaluate relieve degree of pain and functional recovery of hip joint, respectively. RESULTS: At 1 month after treatment, there were no significant differences in VAS, hip Harris score and treatment success rate (all P>0.05). At 2 months after treatment, VAS score in observation group (3.20±0.81) was lower than that of control group (3.87±0.61, P=0.002), there were no significant differences in hip Harris score score between observation group (81.93±2.43) and control group (82.12±2.34, P=0.770), the treatment success rate in observation group (58.62%, 17 / 29) was higher than that of control group (29.16%, 7 / 24) (P=0.032). At 6 months after treatment, VAS score in observationgroup (2.24±0.68) was lower than that of control group (3.12±0.53, P<0.001), hip Harris score score in observation group(85.10±1.75) was higher than that of control group (83.66±1.78)(P=0.005), there were no significant differences in treatment success rate between observation group (82.75%, 24 / 29) and control group (62.50%, 15 / 24)(P=0.096). CONCLUSION: In treatment of greater trochanteric pain syndrome, focused extracorporeal shock wave therapy with centrifugal exercise could significantly relieve symptoms of lateral hip pain, improve functional recovery of hip joint with good safety. This treatment strategy is worthy of application and promotion in clinical practice.

Neuropathology of a remarkable case of memory impairment informs human memory.

Kent Cochrane (K.C.) has been investigated by researchers for nearly three decades after intracranial trauma from a motorcycle accident at age 30 resulted in a striking profile of amnesia. K.C. suffered severe anterograde amnesia in both verbal and non-verbal domains which was accompanied by selective retrograde amnesia for personal events experienced prior to the time of his injury (episodic memory), with relative preservation of memory for personal and world facts (semantic memory), and of implicit memory. This pattern of spared and impaired memory extended to spatial memory for large-scale environments and beyond memory to future imagining and decision-making. Post-mortem brain findings at age 62 included moderate diffuse atrophy, left orbitofrontal contusion, left posterior cerebral artery infarct, and left anterior frontal watershed infarct. Notably, there was severe neuronal loss and gliosis of the hippocampi bilaterally. The left hippocampus was severely affected anteriorly and posteriorly, but CA2, CA4, and the dentate gyrus (DG) were focally spared. There was associated degeneration of the left fornix. The right hippocampus showed near complete destruction anteriorly, with relative preservation posteriorly, mainly of CA4 and DG. Bilateral parahippocampal gyri and left anterior thalamus also showed neuron loss and gliosis. There was no evidence of co-existing neurodegenerative phenomena on beta-amyloid, phosphorylated tau, or TDP-43 immunostaining. The extent of damage to medial temporal lobe structures is in keeping with K.C.'s profound anterograde and retrograde amnesia, with the exception of the unexpected finding of preserved CA2/CA4 and DG. K.C.'s case demonstrates that relatively clean functional dissociations are still possible following widespread brain damage, with structurally compromised brain regions unlikely to be critical to cognitive functions found to be intact. In this way, the findings presented here add to K.C.'s significant contributions to our understanding of clinical-anatomical relationships in memory.

Pericollapse Stage of Osteonecrosis of the Femoral Head: A Last Chance for Joint Preservation.

OBJECTIVE: To propose a new definition of the pericollapse stage of osteonecrosis of the femoral head (ONFH) and review its significance in disease diagnosis and treatment selection. DATA SOURCES: A search for eligible studies was conducted in three electronic databases including PubMed, Cochrane Library, and Embase up to August 10, 2018, using the following keywords: "osteonecrosis", "prognosis", and "treatment". STUDY SELECTION: Investigations appraising the clinical signs, symptoms, and imaging manifestations in different stages of ONFH were included. Articles evaluating the prognosis of various joint-preserving procedures were also reviewed. RESULTS: The pericollapse stage refers to a continuous period in the development of ONFH from the occurrence of subchondral fracture to early collapse (<2 mm), possessing specific imaging features that mainly consist of bone marrow edema and joint effusion on magnetic resonance imaging (MRI), crescent signs on X-ray films, and clinical manifestations such as the sudden worsening of hip pain. Accumulating evidence has indicated that these findings may be secondary to the changes after subchondral fractures. Of note, computed tomography provides more information for identifying possible subchondral fractures than does MRI and serves as the most sensitive tool for grading the pericollapse lesion stage. The pericollapse stage may indicate a high possibility of progressive disease but also demonstrates satisfactory long- and medium-term outcomes for joint-preserving techniques. In fact, if the articular surface subsides more than 2 mm, total hip arthroplasty is preferable. CONCLUSIONS: The pericollapse stage with distinct clinical and imaging characteristics provides a last good opportunity for the use of joint-preserving techniques. It is necessary to separate the pericollapse stage as an independent state in evaluating the natural progression of ONFH and selecting an appropriate treatment regimen.

Different changes of microarchitectures of cortical and cancellous bones in sheep femoral head after long-term glucocorticoid interventions.

This study investigatedthe different effects of long-term glucocorticoid (GC) interventions on the microarchitectures of cortical and cancellous bones of the femoral head. Eighteen female skeletal mature sheep were randomly allocated into 3 groups, 6 each. Group 1 received prednisolone interventions (0.60 mg/kg/day, 5 times weekly) for 7 months. Group 2 received the same interventions as Group 1 and then further observed 3 months without interventions. Control Group was left nonintervention. After killing the animals, all femoral heads were scanned by micro-CT to determine their microstructural properties. In cancellous bone of femoral head, GC interventions led to significant decrease of bone volume fraction, trabecular thickness, trabecular separation, but increase of structure model index and bone surface density (p < 0.05). While in cortical bone, there were no differences between the Group 1 and in microstructural properties (p > 0.05) except greater trabecular thickness in the control group. In addition, three months after cessation of glucocorticoid interventions, most microstructural properties of cancellous bone were significant reversed, but not cortical thickness of femoral head. In contrast to cancellous bone, the microarchitectures of cortical bone were not changed obviously after long-term GC interventions.

Reduced substantia innominata volume mediates contributions of microvascular and macrovascular disease to cognitive deficits in Alzheimer's disease.

The relationships between cholinergic system damage and cerebrovascular disease are not entirely understood. Here, we investigate associations between atrophy of the substantia innominata (SI; the origin of cortical cholinergic projections) and measures of large and small vessel disease; specifically, elongation of the juxtaposed internal carotid artery termination and Cholinergic Pathways Hyperintensity scores (CHIPS). The study (n = 105) consisted of patients with Alzheimer's disease (AD) and/or subcortical ischemic vasculopathy, and elderly controls. AD and subcortical ischemic vasculopathy groups showed greater impingement of the carotid termination on the SI and smaller SI volumes. Both carotid termination elongation and CHIPS were associated independently with smaller SI volumes in those with and without AD. Atrophy of the SI mediated effects of carotid termination elongation on language and memory functions and the effect of CHIPS on attention/working memory. In conclusion, SI atrophy was related to cerebrovascular disease of the large and small vessels and to cognitive deficits in people with and without AD.

Effects of Lower Limb Alignment and Tibial Component Inclination on the Biomechanics of Lateral Compartment in Unicompartmental Knee Arthroplasty.

BACKGROUND: Lateral compartmental osteoarthritis (LCOA), a major complication after medial mobile-bearing unicompartmental knee arthroplasty (UKA), is highly associated with the increased stress of the lateral compartment. This study aimed to analyze the effects on the stress and load distribution of the lateral compartment induced by lower limb alignment and coronal inclination of the tibial component in UKA through a finite element analysis. METHODS: Eight three-dimensional models were constructed based on a validated model for analyzing the biomechanical effects of implantation parameters on the lateral compartment after medial Oxford UKA: postoperative lower limb alignment of 3° valgus, neutral and 3° varus, and the inclination of tibial components placed in 4°, 2° valgus, square, and 2° and 4° varus. The contact stress of femoral and tibial cartilage and load distribution were calculated for all models. RESULTS: In the 3° valgus lower limb alignment model, the contact stress of femoral (3.38 MPa) and tibial (3.50 MPa) cartilage as well as load percentage (45.78%) was highest compared to any other model, and was increased by 36.75%, 47.70%, and 27.63%, respectively when compared to 3° varus. In the condition of a neutral position, the outcome was comparable for the different tibial tray inclination models. The inclination did not greatly affect the lateral compartmental stress and load distribution. CONCLUSIONS: This study suggested that slightly varus (undercorrection) lower limb alignment might be a way to prevent LCOA in medial mobile-bearing UKA. However, the inclination (4° varus to 4° valgus) of the tibial component in the coronal plane would not be a risk factor for LCOA in neutral position.

Significance of Lateral Pillar in Osteonecrosis of Femoral Head: A Finite Element Analysis.

BACKGROUND: The lateral pillar of the femoral head is an important site for disease development such as osteonecrosis of the femoral head. The femoral head consists of medial, central, and lateral pillars. This study aimed to determine the biomechanical effects of early osteonecrosis in pillars of the femoral head via a finite element (FE) analysis. METHODS: A three-dimensional FE model of the intact hip joint was constructed from the image data of a healthy control. Further, a set of six early osteonecrosis models was developed based on the three-pillar classification. The von Mises stress and surface displacements were calculated for all models. RESULTS: The peak values of von Mises stress in the cortical and cancellous bones of normal model were 6.41 MPa and 0.49 MPa, respectively. In models with necrotic lesions in the cortical and cancellous bones, the von Mises stress and displacement of lateral pillar showed significant variability: the stress of cortical bone decreased from 6.41 MPa to 1.51 MPa (76.0% reduction), while cancellous bone showed an increase from 0.49 MPa to 1.28 MPa (159.0% increase); surface displacements of cortical and cancellous bones increased from 52.4 µm and 52.1 µm to 67.9 µm (29.5%) and 61.9 µm (18.8%), respectively. In addition, osteonecrosis affected not only pillars but also adjacent structures in terms of the von Mises stress and surface displacement levels. CONCLUSIONS: This study suggested that the early-stage necrosis in the femoral head could increase the risk of collapse, especially in lateral pillar. On the other hand, the cortical part of lateral pillar was found to be the main biomechanical support of femoral head.

Corticosteroid-induced Osteonecrosis of the Femoral Head: Detection, Diagnosis, and Treatment in Earlier Stages.

OBJECTIVE: This review aimed to provide a current recommendation to multidisciplinary physicians for early detection, diagnosis, and treatment of corticosteroid-induced osteonecrosis of the femoral head (ONFH) based on a comprehensive analysis of the clinical literature. DATA SOURCES: For the purpose of collecting potentially eligible articles, we searched for articles in the PubMed, Cochrane Library, Embase, and CNKI databases up to February 2017, using the following key words: "corticosteroid", "osteonecrosis of the femoral head", "risk factors", "diagnosis", "prognosis", and "treatment". STUDY SELECTION: Articles on relationships between corticosteroid and ONFH were selected for this review. Articles on the diagnosis, prognosis, and intervention of earlier-stage ONFH were also reviewed. RESULTS: The incidence of corticosteroid-induced ONFH was associated with high doses of corticosteroids, and underlying diseases in certain predisposed individuals mainly occurred in the first 3 months of corticosteroid prescription. The enhanced awareness and minimized exposure to the established risk factors and earlier definitive diagnosis are essential for the success of joint preservation. When following up patients with ONFH, treatment should be started if necessary. Surgical treatment yielded better results than conservative therapy in earlier-stage ONFH. The ideal purpose of earlier intervention and treatment is permanent preservation of the femoral head without physical restrictions in daily living. CONCLUSIONS: Clinicians should enhance their precaution awareness of corticosteroid-induced ONFH. For high-risk patients, regular follow-up is very important in the 1st year after high-dose prescription of corticosteroids. Patients with suspected ONFH should be referred to orthopedists for diagnosis and treatment in its earlier stage to preserve the joint.

Collagenosis of the Deep Medullary Veins: An Underrecognized Pathologic Correlate of White Matter Hyperintensities and Periventricular Infarction?

White matter hyperintensities (WMH) are prevalent. Although arteriolar disease has been implicated in their pathogenesis, venous pathology warrants consideration. We investigated relationships of WMH with histologic venous, arteriolar and white matter abnormalities and correlated findings with premortem neuroimaging. Three regions of periventricular white matter were sampled from archived autopsy brains of 24 pathologically confirmed Alzheimer disease (AD) and 18 age-matched nonAD patients. Using trichrome staining, venous collagenosis (VC) of periventricular veins (<150 µm in diameter) was scored for severity of wall thickening and occlusion; percent stenosis by collagenosis of large caliber (>200 µm) veins (laVS) was measured. Correlations were made between WMH in premortem neuroimaging and vascular and white matter pathology. We found greater VC (U(114) = 2092.5, p = 0.005 and U(114) = 2121.5, p = 0.002 for small and medium caliber veins, respectively) and greater laVS (t(110) = 3.46, p = 0.001) in patients with higher WMH scores; WMH scores correlated with VC (rs(114) = 0.27, p = 0.004) and laVS (rs(110) = 0.38, p < 0.001). By multiple linear regression analysis, the strongest predictor of WMH score was laVS (ß = 0.338, p < 0.0001). VC was frequent in patients with periventricular infarcts identified on imaging. We conclude that periventricular VC is associated with WMH in both AD and nonAD patients and the potential roles of VC in WMH pathogenesis merit further study.

Four Methods for Calculating Blood-loss after Total Knee Arthroplasty.

BACKGROUND: Currently, various calculation methods for evaluating blood-loss in patients with total knee arthroplasty (TKA) are applied in clinical practice. However, different methods may yield different results. The purpose of this study was to determine the most reliable method for calculating blood-loss after primary TKA. METHODS: We compared blood-loss in 245 patients who underwent primary unilateral TKA from February 2010 to August 2011. We calculated blood-loss using four methods: Gross equation, hemoglobin (Hb) balance, the Orthopedic Surgery Transfusion Hemoglobin European Overview (OSTHEO) formula, and Hb-dilution. We determined Pearson's correlation coefficients for the four methods. RESULTS: There were large differences in the calculated blood-loss obtained by the four methods. In descending order of combined correlation coefficient based on calculated blood-loss, the methods were Hb-balance, OSTHEO formula, Hb-dilution, and Gross equation. CONCLUSIONS: The Hb-balance method may be the most reliable method of estimating blood-loss after TKA.

[Minimally invasive percutaneous plate osteosynthesis versus open reduction and internal fixation for distal tibial fractures in adults: a meta-analysis].

OBJECTIVE: To perform a meta-analysis on clinical outcomes of minimally invasive percutaneous plate osteosynthesis (MIPPO) or open reduction and internal fixation (ORIF) for distal tibial fractures in adults. METHODS: Pubmed database (from 1968 to March 2014), Cochrane library and CNKI database (from 1998 to March 2014) were searched. Case-control study on minimally invasive percutaneous plate osteosynthesis (MIPPO) or open reduction and internal fixation (ORIF) for distal tibial fractures in adults were chosen,and postoperative infection, operative time, blood loss, fracture nonunion rate, delayed union,fracture malunion rate were seen as evaluation index for meta analysis. The system review was performed using the method recommended by the Cochrane Collaboration. RESULTS: Totally 5 studies (366 patients) were enrolled. Meta-analysis showed that there were significant meaning in postoperative infection between MIPPO and ORIF [OR = 0.23,95% CI (0.06,0.92), P = 0.04]; fracture nonunion rate in MIPPO was lower than in ORIF group [OR = 0.16, 95% CI (0.03,0.76), P = 0.02]; operative time in MIPPO was shorter than in ORIF group, and had significant difference [MD = -14.42, 95% CI (-27.79, -1.05), P < 0.05]; blood loss in MIPPO was less than in ORIF group [MD= -87.17,95%CI (-99.20, -75.15), P < 0.05]; there was no obviously meaning in delayed union between two groups. CONCLUSION: For distal tibial fractures in adults, MIPPO has, advantages of short operative time, less blood loss, lower incidence of infection and fracture non-uniom, but with high fracture malunion rate. MIPPO for distal tibial fractures in adults is better than ORIF, and the best treatment should choose according to patient's condition.

Trail Making Test Elucidates Neural Substrates of Specific Poststroke Executive Dysfunctions.

BACKGROUND AND PURPOSE: Poststroke cognitive impairment is typified by prominent deficits in processing speed and executive function. However, the underlying neuroanatomical substrates of executive deficits are not well understood, and further elucidation is needed. There may be utility in fractionating executive functions to delineate neural substrates. METHODS: One test amenable to fine delineation is the Trail Making Test (TMT), which emphasizes processing speed (TMT-A) and set shifting (TMT-B-A difference, proportion, quotient scores, and TMT-B set-shifting errors). The TMT was administered to 2 overt ischemic stroke cohorts from a multinational study: (1) a chronic stroke cohort (N=61) and (2) an acute-subacute stroke cohort (N=45). Volumetric quantification of ischemic stroke and white matter hyperintensities was done on magnetic resonance imaging, along with ratings of involvement of cholinergic projections, using the previously published cholinergic hyperintensities projections scale. Damage to the superior longitudinal fasciculus, which colocalizes with some cholinergic projections, was also documented. RESULTS: Multiple linear regression analyses were completed. Although larger infarcts (ß=0.37, P<0.0001) were associated with slower processing speed, cholinergic hyperintensities projections scale severity (ß=0.39, P<0.0001) was associated with all metrics of set shifting. Left superior longitudinal fasciculus damage, however, was only associated with the difference score (ß=0.17, P=0.03). These findings were replicated in both cohorts. Patients with ≥2 TMT-B set-shifting errors also had greater cholinergic hyperintensities projections scale severity. CONCLUSIONS: In this multinational stroke cohort study, damage to lateral cholinergic pathways and the superior longitudinal fasciculus emerged as significant neuroanatomical correlates for executive deficits in set shifting.

Kynurenine and depressive symptoms in a poststroke population.

BACKGROUND AND PURPOSE: Depression is a commonly occurring and persistent sequel of stroke affecting approximately 29% of patients. An immunological hypothesis has been put forward, and synthesis of kynurenine from tryptophan has been proposed to link inflammatory activity with neurotoxicity and neurotransmitter dysfunction. This study assessed the relationship between peripheral blood kynurenine and poststroke depressive symptoms. PATIENTS AND METHODS: This was a multisite cross-sectional observational cohort study of patients with ischemic stroke. Depressive symptoms were assessed using the Center for Epidemiological Studies Depression (CES-D) scale and divided into high, medium, and low depressive symptom tertiles. Concentrations of kynurenine and tryptophan were assayed from fasting serum samples, and the kynurenine/tryptophan ratio was compared between tertiles. Serum cytokine concentrations were assayed in a subgroup of patients, and the ratio of proinflammatory (IL-6, IL-18, IFNγ, TNF, IL-1ß) to anti-inflammatory (IL-10) cytokines compared. NLM IDENTIFIER: NCT00254020. RESULTS: In these patients (n=86, 52.3% male, mean age 71.7±14.2 years), there were no differences in kynurenine/tryptophan ratios between CES-D scale tertiles (F 2,76=0.04, P=0.96) controlling for relevant covariates. For cytokines (n=53), serum IL-1ß concentrations (F 2,52=3.55, P=0.037) and serum ratios of IL-18/IL-10 (F 2,52=3.30, P=0.046), IFNγ/IL-10 (F 2,52=4.02, P=0.025), and IL-1ß/IL-10 (F 2,52=4.34, P=0.019) were elevated in the middle CES-D tertile. Post hoc analyses suggested that serum ratios of IL-18/IL-10 (ρ=0.28, P=0.04), and IL-1ß/IL-10 (ρ=0.43, P=0.001), as well as IL-1ß (ρ=0.29, P=0.04), were significantly associated with fatigue. CONCLUSION: Peripheral kynurenine/tryptophan ratios were not associated with depressive symptoms in a poststroke population. However, in exploratory analyses a proinflammatory bias was identified specifically in patients with mild depressive symptoms and associated with poststroke fatigue, suggesting an avenue for future research.

Is encroachment of the carotid termination into the substantia innominata associated with its atrophy and cognition in Alzheimer's disease?

The internal carotid artery termination (CAT) ends in a T-shaped bifurcation just below the substantia innominata (SI), which contains cognitively strategic cholinergic neurons and undergoes atrophy in Alzheimer's disease (AD). This study investigated whether an elongated CAT with possible resulting encroachment into the SI would correlate with SI atrophy and with cognitive dysfunction in AD. We rated the degree of CAT encroachment upon the SI and measured SI volume on magnetic resonance imaging in 30 AD patients, 30 AD patients with subcortical small vessel disease, and 30 age-matched controls. CAT encroachment significantly correlated with SI volume after adjusting for age within the overall group and the groups with dementia. AD patients with higher CAT encroachment scores had lower SI volumes and lower attention, memory, and executive test scores. These data suggest that CAT encroachment may mechanically injure the SI, exacerbating cholinergic damage and contributing to cognitive impairment. This process may represent a possible previously underappreciated mechanism for interaction between large-vessel cerebrovascular disease and AD.

A direct morphometric comparison of five labeling protocols for multi-atlas driven automatic segmentation of the hippocampus in Alzheimer's disease.

Hippocampal volumetry derived from structural MRI is increasingly used to delineate regions of interest for functional measurements, assess efficacy in therapeutic trials of Alzheimer's disease (AD) and has been endorsed by the new AD diagnostic guidelines as a radiological marker of disease progression. Unfortunately, morphological heterogeneity in AD can prevent accurate demarcation of the hippocampus. Recent developments in automated volumetry commonly use multi-template fusion driven by expert manual labels, enabling highly accurate and reproducible segmentation in disease and healthy subjects. However, there are several protocols to define the hippocampus anatomically in vivo, and the method used to generate atlases may impact automatic accuracy and sensitivity - particularly in pathologically heterogeneous samples. Here we report a fully automated segmentation technique that provides a robust platform to directly evaluate both technical and biomarker performance in AD among anatomically unique labeling protocols. For the first time we test head-to-head the performance of five common hippocampal labeling protocols for multi-atlas based segmentation, using both the Sunnybrook Longitudinal Dementia Study and the entire Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) baseline and 24-month dataset. We based these atlas libraries on the protocols of (Haller et al., 1997; Killiany et al., 1993; Malykhin et al., 2007; Pantel et al., 2000; Pruessner et al., 2000), and a single operator performed all manual tracings to generate de facto "ground truth" labels. All methods distinguished between normal elders, mild cognitive impairment (MCI), and AD in the expected directions, and showed comparable correlations with measures of episodic memory performance. Only more inclusive protocols distinguished between stable MCI and MCI-to-AD converters, and had slightly better associations with episodic memory. Moreover, we demonstrate that protocols including more posterior anatomy and dorsal white matter compartments furnish the best voxel-overlap accuracies (Dice Similarity Coefficient=0.87-0.89), compared to expert manual tracings, and achieve the smallest sample sizes required to power clinical trials in MCI and AD. The greatest distribution of errors was localized to the caudal hippocampus and the alveus-fimbria compartment when these regions were excluded. The definition of the medial body did not significantly alter accuracy among more comprehensive protocols. Voxel-overlap accuracies between automatic and manual labels were lower for the more pathologically heterogeneous Sunnybrook study in comparison to the ADNI-1 sample. Finally, accuracy among protocols appears to significantly differ the most in AD subjects compared to MCI and normal elders. Together, these results suggest that selection of a candidate protocol for fully automatic multi-template based segmentation in AD can influence both segmentation accuracy when compared to expert manual labels and performance as a biomarker in MCI and AD.

Complexity of MRI white matter hyperintensity assessments in relation to cognition in aging and dementia from the Sunnybrook Dementia Study.

PURPOSE: Quantification methods for white matter hyperintensities (WMH) on Magnetic Resonance Imaging are heterogeneous, deterring their application. This study compared three WMH rating scales, varying in complexity, and a volumetric method, to evaluate trade-offs between complexity and clinical utility in differentiating dementia subgroups and in correlating with cognition. METHODS: WMH were rated using the Fazekas, Age-Related White Matter Changes (ARWMC) and Scheltens scales, and segmented by computational volumetry in 108 patients with Alzheimer's Disease (AD), 23 with Mild Cognitive Impairment (MCI) and 34 normal controls (NC). Global and hippocampal atrophy, age and education, were accounted for in correlations of WMH with cognitive domains. RESULTS: Intra- and inter-rater reliability were high (intraclass correlation coefficients = 0.88-0.97) across rating scales. WMH scores of all scales were highly correlated with volumes (Spearman r = 0.78-0.90, Ps < 0.001), as well as with each other (Spearman r = 0.86-0.91, Ps < 0.001). The Fazekas scale showed significant separation between AD, MCI and NC using non-parametric analysis, while the ARWMC and Scheltens' scales, and WMH volumes demonstrated significant correlations (standardized ß = -0.19 to -0.24, Ps < 0.05) with cognitive domain scores using multivariate regression analysis, controlling for age, education, global and hippocampal atrophy in patients with AD. CONCLUSIONS: This study suggests that the degree of complexity of WMH rating scales did not affect validation against WMH volumes, but did vary in validation against cognition. The simplest scale performed best in separating cognitive subgroups, but the more complex scales and quantification correlated better with cognitive measures, especially executive function. Hence the best choice of scale depends on the particular application.