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The ABCB1 gene, coding for the efflux transporter P-glycoprotein (PGP), is a candidate gene for Alzheimer disease (AD). P-glycoprotein is heavily expressed at the blood-brain barrier, where it mediates the efflux of β-amyloid (Aβ) from the brain. In this study, we investigated a possible association between 2 common ABCB1 polymorphisms, G2677T/A (Ala893Ser/Thr) and C3435T, AD, and cerebrospinal fluid (CSF) levels of Aβ. No strong evidence for association was found. [ABSTRACT FROM AUTHOR]

Objectives: Agitation/aggression in Alzheimer disease (AD) is a major cause of patient distress, caregiver burden, and institutionalization. Enhanced behavioral responsiveness to central nervous system norepinephrine (NE) release may contribute to the pathophysiology of agitation/aggression in AD. Prazosin, a nonsedating generic medication used for hypertension and benign prostatic hypertrophy, antagonizes NE effects at brain postsynaptic alpha-1 adrenoreceptors. This pilot study examined the efficacy and tolerability of prazosin for behavioral symptoms in patients with agitation/aggression in AD.Design: Double-blind, placebo controlled, parallel group study.Setting: A university AD center and a nursing home in Seattle, WA.Participants: Twenty-two nursing home and community-dwelling participants with agitation/aggression and probable or possible AD (mean age: 80.6 +/- 11.2).Intervention: Randomization to placebo (N = 11) or prazosin (N = 11). Medication was initiated at 1 mg/day and increased up to 6 mg/day using a flexible dosing algorithm.Measurements: The Brief Psychiatric Rating Scale (BPRS) and Neuropsychiatric Inventory (NPI) at Weeks 1, 2, 4, 6, and 8. The Clinical Global Impression of Change (CGIC) at Week 8.Results: Participants taking prazosin (mean dose: 5.7 +/- 0.9 mg/day) had greater improvements than those taking placebo (mean dose: 5.6 +/- 1.2 mg/day) on the NPI (mean change: -19 +/- 21 versus -2 +/- 15, chi = 6.32, df = 1, p = 0.012) and BPRS (mean change: -9 +/- 9 versus -3 +/- 5, chi = 4.42, df = 1, p = 0.036) based on linear mixed effects models and the CGIC (mean: 2.6 +/- 1.0 versus 4.5 +/- 1.6, z = 2.57, p = 0.011 [Mann-Whitney test]). Adverse effects and blood pressure changes were similar between prazosin and placebo groups.Conclusion: Prazosin was well tolerated and improved behavioral symptoms in patients with agitation/aggression in AD. [ABSTRACT FROM AUTHOR]

We hypothesized an association between foot type, foot deformity, and foot ulceration and conducted an analysis of a well-characterized, high-risk diabetic population of 398 subjects. The average age was 62 years of age and 74% of the study population were males. Foot-type distributions were 19.5% pes cavus (high arch), 51.5% neutrally aligned (normal arch), and 29.0% pes planus (low arch). We quantified the presence of hallux valgus (23.9%), hammer/claw toes (46.7%), and hallux limitus (24.4%). A significant association was found between foot type and hallux valgus (p = 0.003); pes planus feet had the highest prevalence as compared with neutrally aligned feet (odds ratio [OR] = 2.43, p = 0.0006). Foot type was also significantly associated with fixed hammer/claw toes (p = 0.01); pes cavus feet had the highest prevalence as compared with neutrally aligned feet (OR = 3.89, p = 0.001). Foot type was also significantly associated with hallux limitus (p = 0.006) with pes planus feet having the highest prevalence as compared with neutrally aligned feet (OR = 2.19, p = 0.003). However, foot type was not significantly related to any ulcer outcome (p = 0.7). Fixed hammer/claw toes (OR = 3.91, p = 0.003) and hallux limitus (OR = 3.02, p = 0.006) were associated with increased risk of any ulcer occurrence. This study affirms that foot type and foot deformity are related and that foot deformities are associated with ulcer occurrence. [ABSTRACT FROM AUTHOR]

To achieve more objective and repeatable measurements of equinus contracture, we developed the equinometer, a device that allows the measurement of ankle range of motion under controlled torque conditions. This study assessed its accuracy across different subjects and examiners. Two examiners used the equinometer to measure the angle of ankle dorsiflexion at 15 N x m torque on five subjects. Accounting for variation in measurements because of subjects, examiners, and placement of device, we used linear mixed-effects models. Accounting for the variation because of subject, different placements of the equinometer within each subject and the adjustment for the effects of examiner and trial sequence, the standard deviation was 0.94 degrees, 95% confidence interval (0.79 degrees, 1.13 degrees). An upper standard deviation of 1.36 degrees is felt to be acceptable for clinical investigation. [ABSTRACT FROM AUTHOR]

Objective: The study objective was to examine the associations among visceral fat (VF), all-cause mortality, and obesity-related mortality.Research Design and Methods: A total of 733 Japanese Americans were followed for 16.9 years. Hazard ratios (HRs) per interquartile range increase in VF were calculated using time-dependent Cox proportional hazard models censored at age 82 years, with age as the time axis adjusted for sex and smoking.Results: Higher VF was associated with all-cause mortality (HR 1.39 [95% CI 1.11-1.75] 107 deaths) and obesity-related mortality (1.39 [1.04-1.85], 68 deaths from cardiovascular disease, diabetes, or obesity-related cancer). After further adjustment for waist circumference, VF remained significantly associated with all-cause mortality (1.41 [1.04-1.92]) but not with obesity-related mortality. The associations between mortality and VF were not independent of BMI.Conclusions: VF was associated with all-cause mortality and obesity-related mortality in Japanese Americans. VF did not significantly improve mortality risk assessment beyond that of BMI. [ABSTRACT FROM AUTHOR]

Amputees lack movement and control mechanisms at the foot and ankle that result in different strategies for locomotion than nonamputees. The torsion adapter is a prosthetic device designed to minimize shear stress at the residual limb by facilitating rotation in the transverse plane. This study determined if the addition of a torsion adapter alters lower-limb joint rotation moments of transtibial amputees walking in a straight line and turning. Ten transtibial amputees wore either a torsion adapter or a rigid adapter for an acclimation period of 3 weeks in random order. Ten nonamputees were also included for comparison. Kinetics were collected as participants walked in a straight line and around a 1 m-radius circular path at their self-selected turning walking speed. When amputee participants wore the torsion adapter, they demonstrated decreased prosthetic-limb peak internal rotation moments at the inside limb knee and hip compared with when they wore the rigid adapter, which may facilitate changes in orientation by not actively resisting the turn. Nonamputees exhibited larger moments compared with the prosthetic limb for both the amputee participants wearing either the torsion or rigid adapters. No differences were found in the moments for the intact limb between torsion and rigid adapter conditions during turning and for both limbs during straight-line walking. [ABSTRACT FROM AUTHOR]

Background: Plantar ulceration is a serious complication of diabetes. However, the mechanism of injury initiating ulceration remains unclear. The unique structure of the plantar soft tissue includes superficial and deep layers of adipocytes contained in septal chambers, however, the size of these chambers has not been quantified in diabetic or non-diabetic tissue. Computer-aided methods can be leveraged to guide microstructural measurements and differences with disease status., Methods: Adipose chambers in whole slide images of diabetic and non-diabetic plantar soft tissue were segmented with a pre-trained U-Net and area, perimeter, and minimum and maximum diameter of adipose chambers were measured. Whole slide images were classified as diabetic or non-diabetic using the Axial-DeepLab network, and the attention layer was overlaid on the input image for interpretation., Results: Non-diabetic deep chambers were 90 %, 41 %, 34 %, and 39 % larger in area (26,954 ± 2428 µm 2 vs 14,157 ± 1153 µm 2 ), maximum (277 ± 13 µm vs 197 ± 8 µm) and minimum (140 ± 6 µm vs 104 ± 4 µm) diameter, and perimeter (405 ± 19 µm vs 291 ± 12 µm), respectively, than the superficial (p < 0.001). However, there was no significant difference in these parameters in diabetic specimens (area 18,695 ± 2576 µm 2 vs 16627 ± 130 µm 2 , maximum diameter 221 ± 16 µm vs 210 ± 14 µm, minimum diameter 121 ± 8 µm vs 114 ± 7 µm, perimeter 341 ± 24 µm vs 320 ± 21 µm). Between diabetic and non-diabetic chambers, only the maximum diameter of the deep chambers differed (221 ± 16 µm vs 277 ± 13 µm). The attention network achieved 82 % accuracy on validation, but the attention resolution was too coarse to identify meaningful additional measurements., Conclusions: Adipose chamber size differences may provide a basis for plantar soft tissue mechanical changes with diabetes. Attention networks are promising tools for classification, but additional care is required when designing networks for identifying novel features., Data Availability: All images, analysis code, data, and/or other resources required to replicate this work are available from the corresponding author upon reasonable request., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a dementia-related proteinopathy common in the elderly population. LATE-NC stages 2 or 3 are consistently associated with cognitive impairment. A condensed protocol (CP) for the assessment of Alzheimer disease neuropathologic change and other disorders associated with cognitive impairment, recommended sampling of small brain portions from specific neuroanatomic regions that were consolidated, resulting in significant cost reduction. Formal evaluation of the CP for LATE-NC staging was not previously performed. Here, we determined the ability of the CP to identify LATE-NC stages 2 or 3. Forty brains donated to the University of Washington BioRepository and Integrated Neuropathology laboratory with known LATE-NC status were resampled. Slides containing brain regions required for LATE-NC staging were immunostained for phospho-TDP-43 and reviewed by 6 neuropathologists blinded to original LATE-NC diagnosis. Overall group performance distinguishing between LATE-NC stages 0-1 and 2-3 was 85% (confidence interval [CI]: 75%-92%). We also used the CP to evaluate LATE-NC in a hospital autopsy cohort, in which LATE-NC was more common in individuals with a history of cognitive impairment, older age, and/or comorbid hippocampal sclerosis. This study shows that the CP can effectively discriminate higher stages of LATE-NC from low or no LATE-NC and that it can be successfully applied in clinical practice using a single tissue block and immunostain., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Evaluate the efficacy and tolerability of prazosin for prophylaxis of headaches following mild traumatic brain injury in active-duty service members and military veterans., Background: Prazosin is an alpha-1 adrenoreceptor antagonist that reduces noradrenergic signaling. An open-label trial in which prazosin reduced headache frequency in veterans following mild traumatic brain injury provided the rationale for this pilot study., Methods: A 22-week parallel-group randomized controlled trial  which included 48 military veterans and active-duty service members with mild traumatic brain injury-related headaches was performed. The study design was based on International Headache Society consensus guidelines for randomized controlled trials for chronic migraine. Following a pre-treatment baseline phase, participants with at least eight qualifying headache days per 4 weeks were randomized 2:1 to prazosin or placebo. After a 5-week titration to a maximum possible dose of 5 mg (morning) and 20 mg (evening), participants were maintained on the achieved dose for 12 weeks. Outcome measures were evaluated in 4-week blocks during the maintenance dose phase. The primary outcome measure was change in 4-week frequency of qualifying headache days. Secondary outcome measures were percent participants achieving at least 50% reduction in qualifying headache days and change in Headache Impact Test-6 scores., Results: Intent-to-treat analysis of randomized study participants (prazosin N = 32; placebo N = 16) demonstrated greater benefit over time in the prazosin group for all three outcome measures. In prazosin versus placebo participants, reductions from baseline to the final rating period for 4-week headache frequency were -11.9 ± 1.0 (mean ± standard error) versus -6.7 ± 1.5, a prazosin minus placebo difference of -5.2 (-8.8, -1.6 [95% confidence interval]), p = 0.005 and for Headache Impact Test-6 scores were -6.0 ± 1.3 versus +0.6 ± 1.8, a difference of -6.6 (-11.0, -2.2), p = 0.004. The mean predicted percent of participants at 12 weeks with ≥50% reduction in headache days/4 weeks, baseline to final rating, was 70 ± 8% for prazosin (21/30) versus 29 ± 12% for placebo (4/14), odds ratio 5.8 (1.44, 23.6), p = 0.013. The trial completion rate of 94% in the prazosin group (30/32) and 88% in the placebo group (14/16) indicated that prazosin was generally well tolerated at the administered dose regimen. Morning drowsiness/lethargy was the only adverse effect that differed significantly between groups, affecting 69% of the prazosin group (22/32) versus 19% of the placebo group (3/16), p = 0.002., Conclusions: This pilot study provides a clinically meaningful efficacy signal for prazosin prophylaxis of posttraumatic headaches. A larger randomized controlled trial is needed to confirm and extend these promising results., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: Examine relationships between self-perceived irritability, prospective memory, and quality of life (QOL) following mild traumatic brain injury (mTBI). Methods: 75 OEF/OIF/OND-era Veterans (56 deployment-related mTBI; 19 no history of TBI), were administered a battery of neuropsychological tests and self-report measures of mood and QOL. Self-perceived irritability was measured using the Neurobehavioral Symptom Inventory. Prospective memory (PM) was measured using the Memory for Intentions Test (MIST). Results: Self-perceived irritability was significantly higher for Veterans with, versus without, a history of deployment-related mTBI. Among Veterans with a history of mTBI, self-perceived irritability was inversely associated with PM performance, even after adjusting for PTSD severity. Greater self-perceived irritability was also associated with higher depressive symptoms and reduced QOL for perceived physical health, psychological health, social support, and environmental factors; however, only social support remained significant after adjusting for PTSD severity. Depression symptom severity was not significantly associated with PM, suggesting that PM may be uniquely related to self-perceived irritability rather than mood dysregulation more generally. Conclusions: Findings provide preliminary evidence of a relationship between PM and self-perceived irritability in Veterans with a history of mTBI. PM and irritability may be related via their mutual reliance on high-level cognitive control. Results illustrate possible cognitive and affective factors contributing to psychological and interpersonal challenges for this population. Future investigations with larger and more diverse samples are needed to replicate findings and explore potential mechanisms linking irritability and PM following mTBI.

Background: Many patients with dementia with Lewy bodies (DLB) miss out on the best standards of care and psychosocial support due to diagnostic delays or inaccuracies following symptom onset., Objective: This study seeks to identify baseline characteristics in individuals with mild cognitive impairment (MCI) that correlate with eventual conversion to DLB or Alzheimer's disease (AD)., Methods: Baseline neuropsychological and neuropsychiatric data were analyzed in National Alzheimer's Coordinating Center participants who completed the Uniform Data Set between 2006 and 2020 and subsequently converted from MCI to DLB or AD (n = 1632)., Results: Only 6% of participants with MCI converted to DLB. Among those who converted to DLB, multidomain amnestic MCI (aMCI) was the most common subtype at study entry. As part of logistic regression analyses, odds ratios (ORs) were estimated for conversion to DLB versus AD based on study-entry characteristics, adjusting for age, sex, education, and years to diagnosis. The strongest predictors of conversion to DLB (p≤0.0001) were nonamnestic MCI versus aMCI (OR 8.2, CI [5.0, 14]), multidomain MCI versus single-domain MCI (OR 2.7, CI [1.7. 4.2]), male sex (OR 4.2, CI [2.5, 7.1]), and presence of nighttime behaviors (OR 4.4 CI [2.8, 6.9])., Conclusion: A diagnosis of prodromal DLB should be considered in individuals with MCI who present with prominent executive/visuospatial deficits, neuropsychiatric symptoms, and less memory impairment. Early diagnosis of DLB may guide treatment planning, including the avoidance of antipsychotic medications in patients who develop psychotic symptoms, caregiver support, and initiation of early treatment(s) once medications become available.

Persons with ankle osteoarthritis (AOA) often seek surgical intervention to alleviate pain and restore function; however, recent research has yielded no superior choice between the two primary options: fusion and replacement. One factor yet to be considered is the effect of footwear on biomechanical outcomes. Comparisons of AOA biomechanics to a normative population are also sparse. The objectives of this study were to (1) determine how footwear uniquely affected gait in persons with ankle fusion and replacement and (2) provide context for AOA biomechanics via comparisons to a healthy adult sample. Thirty-four persons with AOA performed overground walking trials barefoot and shod before surgical intervention and then received either an ankle fusion (n = 14) or replacement (n = 20). Two and/or three years post-surgery, patients returned for gait analysis. Nineteen controls performed the same gait procedures during a single study visit. Spatiotemporal variables and peak angles, internal moments, powers, and forces were calculated to quantify gait behavior. Overall, the two surgical groups performed similarly to each other but demonstrated marked differences from controls both pre- and post-surgery. No significant differences were detected when examining the effect of footwear. The motion of the midfoot with respect to the hindfoot and forefoot may be instrumental in gait biomechanics following an ankle fusion or replacement and should be considered in future investigations., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Ankle coronal plane deformity represents a complex 3-dimensional problem, and comparative data are lacking to guide treatment recommendations for optimal treatment of end-stage ankle arthritis with concomitant coronal plane deformity., Methods: In total, 224 patients treated for end-stage ankle arthritis were enrolled in an observational trial. Of 112 patients followed more than 2 years, 48 patients (19 arthrodesis, 29 arthroplasty) had coronal plane deformity and were compared to 64 patients without coronal plane deformity (18 arthrodesis, 46 arthroplasty) defined as greater than 10 degrees of varus or valgus. The arthroplasty implants used had different internal constraints to intracomponent coronal plane tilting. Patients completed Musculoskeletal Functional Assessment (MFA) and SF-36 preoperatively and at 3, 6, 12, 24, and 36 months postoperatively. Measures included change in SF-36 and MFA, as well as compared reoperation rates and pain scales., Results: For the groups with coronal plane ankle deformity, the median for the arthrodesis group was 19.0 degrees and the median for the arthroplasty group was 16.9 degrees. In the deformity cohort during the follow-up period, we had 7 major reoperations: 2 in the arthrodesis group and 5 in the arthroplasty group, all with the less constrained implant design. MFA, vitality, and social function of the SF-36 improved for all groups. Patients without preoperative deformities had greater improvement with fusion or replacement at both 2 and 3 years. There was no difference in improvement between those patients with coronal deformity who received arthroplasty vs arthrodesis., Conclusion: Patients with and without coronal plane deformity may benefit from ankle arthroplasty and arthrodesis, although greater improvements may be expected in those without preoperative deformity. In this study, at final follow-up of 3 years, overall we found no meaningful difference in patient-reported outcomes between the patients with preoperative coronal plane deformities whether they had a fusion or a replacement as treatment for end-stage ankle arthritis., Level of Evidence: Level II, comparative study.

Background: The rate of total ankle arthroplasty (TAA) is increasing relative to ankle arthrodesis (AA) for patients seeking surgical treatment for end-stage ankle arthritis. Patients and providers would benefit from a more complete understanding of the rate of improvement, the average length of time to achieve maximal function and minimal pain, and whether there is a greater decline in function or an increase in pain over time following TAA compared with AA. The objectives of this study were to compare treatment changes in overall physical and mental function and ankle-specific function, as well as pain intensity at 48 months after TAA or AA in order to determine if the improvements are sustained., Methods: This was a multisite prospective cohort study that included 517 participants (414 TAA and 103 AA) who presented for surgical treatment. Participants were compared 48 months after surgery using the Foot and Ankle Ability Measure (FAAM) Activities of Daily Living and Sports subscales (0 to 100 points), the Short Form-36 (SF-36) Physical and Mental Component Summary (PCS and MCS) scores (0 to 100 points), and pain scores (0 to 10 points)., Results: Both groups achieved significant improvement in the 2 FAAM measures, the SF-36 PCS score, and all of the pain measures at 48 months after surgey (p < 0.001). Mean improvements from baseline in patients undergoing TAA for the FAAM Activities of Daily Living, FAAM Sports, and SF-36 scores were at least 9 points, 8 points, and 3.5 points, respectively, which were higher than in those undergoing AA. Mean improvements in worst and average pain were at least 0.9 point higher in patients undergoing TAA than in those undergoing AA at 12, 24, and 36 months. These differences were attenuated by 48 months. For both treatments, all improvements from baseline to 24 months had been maintained at 48 months., Conclusions: When both procedures are performed by the same group of surgeons, patients who undergo TAA or AA for end-stage ankle arthritis have significant improvement in overall function, ankle-specific function, and pain at 48 months after surgery, with better functional improvement in the TAA group., Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: This project was funded by National Institutes of Health (NIH) grant number R01 AR056316. The NIH played no role in the investigation. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work and “yes” to indicate that the author had other relationships or activities that could be perceived to influence, or have the potential to influence, what was written in this work (http://links.lww.com/JBJS/G380)., (Copyright © 2021 Written work prepared by employees of the Federal Government as part of their official duties is, under the United States Copyright Act, a ‘work of the United States Government’ for which copyright protection under that Act is not available. As such, copyright protection does not extend to the contributions of employees of the Federal Government prepared as part of their employment.)

Background: Prosthetic feet are available in a range of stiffness categories, however, there is limited evidence to guide optimal selection during prosthetic foot prescription. The aim of this study was to determine the effect of commercial prosthetic foot stiffness category on foot-ankle biomechanics, gait symmetry, community ambulation, and relative foot stiffness perception., Methods: Participants were fit in randomized order with three consecutive stiffness categories of a commonly-prescribed prosthetic foot. Prosthetic foot roll-over shape and ankle push-off power and work were determined via data collected during walking in a motion analysis laboratory. Step activity was recorded during community use of each foot. Self-reported perception of relative foot stiffness was assessed with an ad hoc survey., Findings: Seventeen males with transtibial amputation completed the study. Prosthetic foot roll-over radius increased with increased prosthetic foot stiffness categories (p < 0.001). Both prosthetic ankle push-off peak power and work decreased with increased foot stiffness categories (p = 0.002). There was no association between prosthetic foot stiffness category and step length symmetry or steps per day. When assessed post-accommodation, there was no association between relative foot stiffness perception and the stiffness category across prosthetic foot conditions., Interpretation: Prosthetic foot stiffness category was significantly associated with changes in prosthetic foot-ankle biomechanical variables, however, was not associated with changes in gait symmetry or community ambulation. Relative prosthetic foot stiffness perception after accommodation was generally inconsistent with the order of prosthetic foot stiffness categories., Clinical Relevance: While there were quantifiable differences in prosthetic foot-ankle biomechanics across stiffness categories, no significant differences were detected in gait symmetry or mean daily step count in the community. Furthermore, after community use, participants perceptions of relative stiffness across feet were generally inconsistent with the order of prosthetic foot stiffness categories. These findings raise questions as to whether changes in commercial prosthetic foot stiffness category (within a clinically relevant range) affect subjective and objective measures relevant to successful outcomes from prosthetic foot prescription., (Published by Elsevier Ltd.)

Background: The objective of this study was to explore the relationships between claw toe deformity, peripheral neuropathy, intrinsic muscle volume, and plantar aponeurosis thickness using computed tomography (CT) images of diabetic feet in a cross-sectional analysis., Methods: Forty randomly-selected subjects with type 2 diabetes were selected for each of the following four groups (n = 10 per group): 1) peripheral neuropathy with claw toes, 2) peripheral neuropathy without claw toes, 3) non-neuropathic with claw toes, and 4) non-neuropathic without claw toes. The intrinsic muscles of the foot were segmented from processed CT images. Plantar aponeurosis thickness was measured in the reformatted sagittal plane at 20% of the distance from the most inferior point of the calcaneus to the most inferior point of the second metatarsal. Five measurement sites in the medial-lateral direction were utilized to fully characterize the plantar aponeurosis thickness. A linear mixed-effects analysis on the effects of peripheral neuropathy and claw toe deformity on plantar aponeurosis thickness and intrinsic muscle volume was performed., Results: Subjects with concurrent neuropathy and claw toes had thicker mean plantar aponeurosis (p < 0.006) and may have had less mean intrinsic muscle volume (p = 0.083) than the other 3 groups. The effects of neuropathy and claw toes on aponeurosis thickness were synergistic rather than additive. A similar pattern may exist for intrinsic muscle volume, but results were not as conclusive. A negative correlation was observed between plantar aponeurosis thickness and intrinsic muscle volume (R 2  = 0.323, p < 0.001)., Conclusions: Subjects with concurrent neuropathy and claw toe deformity were associated with the smallest intrinsic foot muscle volumes and the thickest plantar aponeuroses. Intrinsic muscle atrophy and plantar aponeurosis thickening may be related to the development of claw toes in the presence of neuropathy.

Introduction : This study investigated variables associated with subjective decline in executive function among Veterans of Operations Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/OIF/OND) following a history of blast-related mild traumatic brain injury (mTBI). Method : Fifty-six male U.S. Veterans ( M Age   = 35.3 ± 8.8 years) with a history of blast-related mTBI (6.6 ± 3.2 years post injury) completed a battery of self-report questionnaires and neuropsychological measures. Participants rated current and retrospectively estimated pre-mTBI executive function difficulties on the Frontal Systems Behavior Scale (FrSBe). A difference score (post- minus pre-mTBI ratings) was the dependent variable (∆FrSBe). Linear regression models examined variables predicting ∆FrSBe, including: pre-injury characteristics (education, premorbid intelligence), injury-related characteristics (number of blast exposures, losses of consciousness), post-injury clinical symptoms (PTSD Checklist-Military version; Pittsburgh Sleep Quality Index), and post-injury neuropsychological performances on executive function measures (Trail Making Test Part B; Controlled Oral Word Association Test; Auditory Consonant Trigrams; Wisconsin Card Sorting Test). Results : While 11% of participants had a clinically elevated pre-injury FrSBe total score, 82% had a clinically elevated post-injury FrSBe total score. Only self-reported PTSD symptom severity independently predicted perceived change in executive function. Conclusions : Many OEF/OIF/OND Veterans with a history of blast-related mTBI experience subjective decline in executive function following injury. Perceived executive function decline was associated with higher PTSD symptom severity, aligning with previous research associating PTSD with cognitive complaints. Results did not support a correspondence between perceived cognitive change and neuropsychological performances.

Background: Newer designs and techniques of total ankle arthroplasty (TAA) have challenged the assumption of ankle arthrodesis (AA) as the primary treatment for end-stage ankle arthritis. The objective of this study was to compare physical and mental function, ankle-specific function, pain intensity, and rates of revision surgery and minor complications between these 2 procedures and to explore heterogeneous treatment effects due to age, body mass index (BMI), patient sex, comorbidities, and employment on patients treated by 1 of these 2 methods., Methods: This was a multisite prospective cohort study comparing outcomes of surgical treatment of ankle arthritis. Subjects who presented after nonoperative management had failed received either TAA or AA using standard-of-treatment care and rehabilitation. Outcomes included the Foot and Ankle Ability Measure (FAAM), Short Form-36 (SF-36) Physical and Mental Component Summary (PCS and MCS) scores, pain, ankle-related adverse events, and treatment success., Results: Five hundred and seventeen participants underwent surgery and completed a baseline assessment. At 24 months, the mean improvement in FAAM activities of daily living (ADL) and SF-36 PCS scores was significantly greater in the TAA group than in the AA group, with a difference between groups of 9 points (95% confidence interval [CI] = 3, 15) and 4 points (95% CI = 1, 7), respectively. The crude incidence risks of revision surgery and complications were greater in the AA group; however, these differences were no longer significant after adjusting for age, sex, BMI, and Functional Comorbidity Index (FCI). The treatment success rate was greater after TAA than after AA for those with an FCI of 4 (80% versus 62%) and not fully employed (81% versus 58%) but similar for those with an FCI score of 2 (81% versus 77%) and full-time employment (79% versus 78%)., Conclusions: At 2-year follow-up, both AA and TAA were effective. Improvement in several patient-reported outcomes was greater after TAA than after AA, without a significant difference in the rates of revision surgery and complications., Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Background: Ambulatory activity is reduced in patients with ankle arthritis. In this study, we measured step activity over time in 2 treatment groups and secondarily compared step activity with results of patient-reported outcome measures (PROMs)., Methods: Patients who were treated with either ankle arthrodesis or ankle arthroplasty wore a step activity monitor preoperatively and at 6, 12, 24, and 36 months postoperatively. Changes from preoperative baseline in total steps per day and per-day metrics of low, medium, and high-activity step counts were measured in both treatment groups. Step activity was compared with each subject's PROM scores as reported on the Musculoskeletal Function Assessment (MFA) and the Short Form-36 (SF-36) physical function and bodily pain subscales., Results: Of the 3 activity levels, combined group high-activity step counts showed the greatest increase (mean of 278 steps [95% confidence interval (CI), 150 to 407 steps], a 46% improvement from preoperatively). At 6 months, the mean high-activity step improvement for the arthroplasty group was 194 steps compared with a mean decline of 44 steps for the arthrodesis group (mean 238-step difference [95% CI, -60 to 536 steps]). By 36 months postoperatively, the greater improvement in high-activity steps for the arthroplasty versus the arthrodesis group was no longer present. There were no significant pairwise differences in improvement based on surgical treatment method at any individual follow-up time point. For a within-patient increase of 1,000 total steps, there was a mean change in the MFA, SF-36 physical function, and SF-36 bodily pain scores of -1.8 (95% CI, -2.4 to -1.2), 3.8 (95% CI, 2.8 to 4.8), and 2.8 (95% CI, 1.8 to 3.9), respectively (p < 0.0001 for all associations). There was no evidence that the association differed by study visit, or by study visit and surgical procedure interaction (p > 0.10)., Conclusions: Surgical treatment of ankle arthritis significantly improves ambulatory activity, with greater change occurring at high activity levels. Improvement may occur more quickly following arthroplasty than arthrodesis, but at 3 years, we detected no significant difference between the 2 procedures. Step counts, while associated with PROMs, do not parallel them, and thus may be a useful supplementary measure, particularly in longitudinal studies., Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Objectives : Mental health factors, such as PTSD, can exacerbate typical age-related cognitive changes and lead individuals to have subjective concerns for which few interventions presently exist. This study evaluates self-reported mental health outcomes following a psychoeducational memory skills program designed for veterans over 50 with subjective memory concerns in the context of PTSD. It was hypothesized that outcomes would improve following program participation and that baseline cognitive self-efficacy would moderate improvements in self-reported depression and life satisfaction. Methods : Veterans ( n = 101, age ≥ 51) participated in an 8-week memory skills program and completed baseline and post-program assessment data as part of a quality improvement project. Results : Life satisfaction and cognitive self-efficacy demonstrated significant improvement following participation in the memory skills program. Cognitive self-efficacy was found to significantly modify change in depressive symptoms. Conclusions : We found improvement in mental health outcomes following participation in a psychoeducational memory skills program, with differential impact on depressive symptoms for those with low baseline cognitive self-efficacy. Clinical Implications : Participation in this intervention led to improved life satisfaction and cognitive self-efficacy. Cognitive self-efficacy, in turn, appeared to have implications for improving depressive symptomology and may be a useful target of memory skills education.

Background: This study summarized the frequency and functional impact of adverse events (AEs) that occur after surgery for end-stage ankle arthritis (ESAA) to inform decision making., Methods: This was a multisite prospective cohort study to compare ankle arthroplasty to ankle arthrodesis in the treatment of ESAA among 6 participating sites. We compared the risk and impact of nonankle AEs and ankle-specific AEs versus no AEs controlling for potential confounding factors, including operative procedure using multinomial logistic regression. We estimated differences in postoperative functional outcomes by AE occurrence using linear mixed effects regression. Among 517 patients who had surgery for ankle arthritis and completed the full baseline assessment, follow-up scores were available in 494 (95%) patients., Results: There were a total of 628 reported AEs (477 in the arthroplasty group and 151 in the arthrodesis group). These occurred in 261 (63%) arthroplasty patients and 67 (65%) arthrodesis patients. There were 50 (8%) ankle-specific AEs. The risk of an ankle-specific AE was slightly higher in the arthrodesis group versus the arthroplasty group, odds ratio (OR) 1.84, 95% confidence interval (CI, 0.85, 3.98). The OR for the risk of non-ankle-specific AE versus no AE was 0.96, 95% CI (0.57, 1.61) for those receiving arthrodesis compared to arthroplasty. Compared to patients with no AEs, those experiencing ankle-specific AEs had significantly less improvement in Foot and Ankle Ability Measure Sports and activities of daily living (ADL) subscores and worst pain outcomes; however, both groups improved significantly in all measures except mental health., Conclusions: Ankle-specific AEs were infrequent and only weakly associated with operative procedure. Although patients improved in all functional outcomes except mental health, regardless of AE occurrence, ankle-specific AEs negatively impacted patient improvement compared to those with no AEs or a nonankle AE. The logistical effort and cost of tracking nonankle AEs does not seem to be justified., Level of Evidence: Level II, prospective comparative study.

Objective: This study evaluated the effects of Alzheimer disease (AD) on the relationship between the brain noradrenergic system and hypothalamic pituitary adrenocortical axis (HPA). Specifically, relationships between cerebrospinal fluid (CSF) norepinephrine (NE) and CSF cortisol were examined in cognitively normal participants and participants with AD dementia and amnestic mild cognitive impairment (aMCI). We hypothesized that there would a positive association between these 2 measures in cognitively normal controls and that this association would be altered in AD., Methods: Four hundred twenty-one CSF samples were assayed for NE and cortisol in controls (n = 305), participants with aMCI (n = 22), and AD dementia (n = 94). Linear regression was used to examine the association between CSF cortisol and NE, adjusting for age, sex, education, and body mass index., Results: Contrary to our hypothesis, CSF cortisol and NE levels were not significantly associated in controls. However, higher cortisol levels were associated with higher NE levels in AD and aMCI participants. Regression coefficients ± standard errors for the change in cortisol per 100-pg/mL increase in NE are as follows: controls 0.0 ± 0.2, P = 1.0; MCI, 1.4 ± 0.7, P = .14; and AD 1.1 ± 0.4, P = .032. Analysis with MCI and AD participants combined strengthened statistical significance (1.2 ± 0.3, P = .007)., Conclusions: Enhanced responsiveness of the HPA axis to noradrenergic stimulatory regulation in AD and disruption of the blood brain barrier may contribute to these findings. Because brainstem noradrenergic stimulatory regulation of the HPA axis is substantially increased by both acute and chronic stress, these findings are also consistent with AD participants experiencing higher levels of acute and chronic stress., (Copyright © 2018 John Wiley & Sons, Ltd.)

Background: Diabetes results in pathophysiological changes, leading to tissue that is unable to withstand and adapt to the same loads, resulting in breakdown. Certain locations are more susceptible to breakdown, yet differences between locations are largely not well understood. The authors performed a histological and biochemical analysis of isolated plantar adipose tissue at six relevant locations., Methods: Tissue from six plantar locations (hallux, first, third and fifth metatarsal heads, lateral midfoot and calcaneus) was taken from fresh cadaveric feet of older diabetic and older non-diabetic intact donors. Histomorphological and biochemical analysis of isolated plantar tissue from both diabetic and non-diabetic feet at six relevant locations was performed., Results: The main differences found between diabetic and non-diabetic tissue were in the thickness of the septal walls and the elastin content. Diabetic tissue had significantly thicker septal walls and an increased elastin concentration. When comparing the calcaneus to other locations, although there were no differences found in the thickness of the septal walls of diabetic tissue, elastin content was lower in the calcaneous tissue compared to the non-calcaneus sites., Conclusions: Modifications in the structural and biochemical properties could translate to changes in the mechanical properties. This information could lead to an understanding of how the structural and biochemical changes result in an increase in susceptibility of tissue to breakdown with load at the different locations of the foot., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background/objectives: Longitudinal studies have shown an increase in cognitive decline many years before clinical diagnosis of dementia. We sought to estimate changes, relative to "normal" aging, in the trajectory of scores on a global cognitive function test-the Cognitive Abilities Screening Instrument (CASI)., Design: A prospective cohort study., Setting: Community-dwelling members of a U.S. health maintenance organization., Participants: Individuals aged 65 and older who had no dementia diagnosis at baseline and had at least two visits with valid CASI test score (N = 4,315)., Measurements: Average longitudinal trajectories, including changes in trajectory before clinical diagnosis in those who would be diagnosed with dementia, were estimated for CASI item response theory (IRT) scores. The impact of sex, education level, and APOE genotype on cognitive trajectories was assessed., Results: Increased cognitive decline relative to "normal" aging was evident in CASI IRT at least 10 years before clinical diagnosis. Male gender, lower education, and presence of ≥1 APOE ε4 alleles were associated with lower average IRT scores. In those who would be diagnosed with dementia, a trajectory change point was estimated at an average of 3.1 years (95% confidence interval 3.0-3.2) before clinical diagnosis, after which cognitive decline appeared to accelerate. The change point did not differ by sex, education level, or APOE ε4 genotype. There were subtle differences in trajectory slopes by sex and APOE ε4 genotype, but not by education., Conclusion: Decline in average global cognitive function was evident at least 10 years before clinical diagnosis of dementia. The decline accelerated about 3 years before clinical diagnosis., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Background: We analyzed self-reported outcomes in a prospective cohort of patients treated with ankle arthrodesis or total ankle replacement (TAR) during a time of transition from older to newer-generation TAR implants., Methods: We performed a prospective cohort study comparing outcomes in 273 consecutive patients treated for ankle arthritis with arthrodesis or TAR between 2005 and 2011. Adult patients with end-stage ankle arthritis who were able to walk and willing and able to respond to surveys were included in the study. Patients were excluded when they had another lower-limb problem that might affect walking. At baseline and at 6, 12, 24, and 36-month follow-up visits, participants completed a pain score, a Musculoskeletal Function Assessment (MFA), and a Short Form-36 (SF-36) survey., Results: There was significant mean improvement in most outcomes after surgery regardless of procedure. In general, the greatest improvement occurred during the first 6 months of follow-up. Linear mixed-effects regression adjusted for differences at baseline in age, body mass index (BMI), and surgery type showed that at 6 months the scores were improved by a mean (and standard error) of 12.6 ± 0.7 (33%) on the MFA, 22.0 ± 1.4 (56%) on the SF-36 Physical Functioning (PF) scale, 32.4 ± 1.6 (93%) on the SF-36 Bodily Pain (BP) scale, and 4.0 ± 0.2 (63%) on the pain rating scale. The mean improvements in the MFA and SF-36 PF scores over the 3-year follow-up period were significantly better after the TARs than after the arthrodeses, with differences between the 2 groups of 3.6 ± 1.6 (p = 0.023) and 7.5 ± 2.9 (p = 0.0098), respectively. The differences between the 2 groups were slightly greater when only the newer TAR devices were compared with the arthrodeses (MFA = 3.8 ± 1.8 [p = 0.031], SF-36 PF = 8.8 ± 3.3 [p = 0.0074], SF-36 BP = 7.3 ± 3.6 [p = 0.045], and pain score = 0.8 ± 0.4 [p = 0.038])., Conclusions: Patients reported improved comfort and function after both surgical treatments. The average improvement in the MFA and SF-36 PF scores was better after TAR than after arthrodesis, particularly when the TAR had been done with later-generation implants. Younger patients had greater functional improvements than older patients., Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Background: This study sought to evaluate gender and APOE genotype-related differences in the concentrations of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) and cerebrovascular injury across the life span of cognitively normal adults., Methods: CSF amyloid beta 1-42 (Aβ 42 ), phospho-tau-181 (p-tau 181 ), and total tau were measured in 331 participants who were between the ages of 21 and 100. CSF E-selectin and vascular cell adhesion protein 1 (VCAM1) were measured in 249 participants who were between the ages of 50 and 100., Results: CSF total tau and p-tau 181 increased with age over the adult life span (p < 0.01) with no gender differences in those increases. CSF Aβ 42 concentration varied according to age, gender, and APOE genotype (interaction of age × gender × ε4, p = 0.047). CSF VCAM1, but not E-selectin, increased with age (p < 0.01), but both were elevated in men compared to women (p < 0.01)., Conclusions: Female APOE-ε4 carriers appear at higher risk for AD after age 50. In contrast, men may experience a relatively higher rate of cerebrovascular injury in middle and early old age.

Concerns regarding resource expenditures have been expressed about the 2012 NIA-AA Sponsored Guidelines for neuropathologic assessment of Alzheimer disease (AD) and related dementias. Here, we investigated a cost-reducing Condensed Protocol and its effectiveness in maintaining the diagnostic performance of Guidelines in assessing AD, Lewy body disease (LBD), microvascular brain injury, hippocampal sclerosis (HS), and congophilic amyloid angiopathy (CAA). The Condensed Protocol consolidates the same 20 regions into 5 tissue cassettes at ∼75% lower cost. A 28 autopsy brain-retrospective cohort was selected for varying levels of neuropathologic features in the Guidelines (Original Protocol), as well as an 18 consecutive autopsy brain prospective cohort. Three neuropathologists at 2 sites performed blinded evaluations of these cases. Lesion specificity was similar between Original and Condensed Protocols. Sensitivities for AD neuropathologic change, LBD, HS, and CAA were not substantially impacted by the Condensed Protocol, whereas sensitivity for microvascular lesions (MVLs) was decreased. Specificity for CAA was decreased using the Condensed Protocol when compared with the Original Protocol. Our results show that the Condensed Protocol is a viable alternative to the NIA-AA guidelines for AD neuropathologic change, LBD, and HS, but not MVLs or CAA, and may be a practical alternative in some practice settings., (© 2017 American Association of Neuropathologists, Inc. All rights reserved.)

Diabetes, and the subsequent complication of lower limb ulcers leading to potential amputation, remains an important health care problem in United States, even with declining amputation rates. It has been well documented that diabetes can alter the mechanical properties (i.e., increased stiffness) of the plantar soft tissue, although this finding is not universal. Similarly, biochemical, and histological changes have been found in the plantar soft tissue, but, as with the mechanical changes, these findings are not consistent across all studies. Our group׳s work has demonstrated that diabetes increases plantar soft tissue modulus and increases elastic septal thickness. The purpose of the current study was to explore the association between mechanical, biochemical and histological properties. Using previously collected data, a linear mixed effects regression was conducted. The correlations were weak; of the 32 that were tested, only 3 (modulus to septal thickness when location was accounted for, energy loss to total collagen, and energy loss to collagen/elastin ratio) were statistically significant, none with an R 2 greater than 0.10. The main differences in the means were increased tissue stiffness and increased septal wall thickness, both trends were supported in the literature. However, as the correlations were weak, it is likely that another unexamined biochemical factor (perhaps collagen crosslinking) is associated with the mechanical tissue changes., Competing Interests: statement The authors have no conflicts to report., (Published by Elsevier Ltd.)

Maintaining balance while walking is challenging for lower limb amputees. The effect of prosthetic foot stiffness on recovery kinetics from an error in foot placement may inform prescription practice and lead to new interventions designed to improve balance. Ten unilateral transtibial amputees were fit with two prosthetic feet with different stiffness properties in random order. After a 3-week acclimation period, they returned to the lab for testing before switching feet. Twelve non-amputees also participated in a single data collection. While walking on an instrumented treadmill, we imposed a repeatable, unexpected medial or lateral disturbance in foot placement by releasing a burst of air at the ankle just before heel strike. Three-dimensional motion capture, ground reaction force and center of pressure (COP) data were collected for two steps prior, the disturbed step and three steps after the disturbance. During undisturbed walking, coronal ankle impulse was lower by 42% for amputees wearing a stiff compared to a compliant foot (p=0.017); however, across steps, both prosthetic recovery patterns were similar compared to the sound limb and non-amputees. Peak coronal hip moment was 15-20% lower for both foot types during undisturbed walking (p<0.001), with less change in response to the medial disturbance (p<0.001) compared to the sound limb and non-amputees. Amputee prosthetic COP excursion was unaffected by the disturbance (2.4% change) compared to the sound limb (59% change; p<0.001) and non-amputees (55% change; p<0.001). These findings imply that a prosthetic foot-ankle system able to contribute to ankle kinetics may improve walking balance among amputees., (Published by Elsevier Ltd.)

Background: The purpose of this study was to identify the effects that X-ray source misalignment has on common measurements made from anterior-poster (AP) and medial-lateral (ML) view foot radiographs., Methods: A cadaveric foot model was used to obtain ML radiographs with ±25 degree transverse plane misalignment. From these images the calcaneal pitch angle (CPA) and lateral talometatarsal angle (LTMA) were measured. AP images were captured with up to 30 degree sagittal plane misalignment as well as ±15 degree misalignment in the transverse plane at each sagittal angle. From these images the talonavicular coverage angle (TNCA) and talometatarsal angle (TMA) were measured., Results: On the ML images, the CPA was sensitive to transverse plane misalignment from -10 to -25 degrees and from 15 to 25 degrees (P < .005). The LTMA was a more reliable measurement than the CPA and did not demonstrate sensitivity to transverse plane misalignment. On the AP images, the TNCA and TMA were not sensitive to sagittal plane misalignment alone. However, at 0, 10, and 15 degrees sagittal misalignment the TNCA showed sensitivity to transverse plane misalignment (P < .0083)., Conclusion: Misalignment of an X-ray source can lead to errors in the measurement of foot radiographic parameters, especially the CPA when there is transverse plane misalignment and the TNCA when there is both sagittal and transverse plane misalignment. The LTMA and TMA can be measured reliably, even with significant misalignment present., Clinical Relevance: If a researcher or clinician is interested in measuring the CPA or TNCA, the current best practices guidelines for obtaining ML and AP images should be closely followed., (© The Author(s) 2014.)

Importance: The Healthy Brain Initiative 2013-2018 seeks to optimize brain health as we age. Free radical injury is an important effector of molecular and cellular stress in the aging brain that derives from multiple sources., Objective: To identify potentially modifiable risk factors associated with increased markers of brain oxidative stress., Design, Setting, and Participants: This cross-sectional, academic multicenter study consisted of 320 research volunteers (172 women) aged 21 to 100 years who were medically healthy and cognitively normal., Main Outcomes and Measures: Free radical injury to the brain was assessed using cerebrospinal fluid (CSF) F2-isoprostane (F2-IsoP) concentrations correlated with age, sex, race, cigarette smoking, body mass index, inheritance of the ε4 allele of the apolipoprotein E gene (APOE), and CSF biomarkers of Alzheimer disease., Results: The concentration of CSF F2-IsoP increased with age by approximately 3 pg/mL (approximately 10%) from age 45 to 71 years in medically healthy, cognitively normal adults (P < .001). The CSF F2-IsoP concentration increased by approximately more than 10% for every 5-U increase in body mass index (P < .001). Current smoking had an approximately 3-fold greater effect on CSF F2-IsoPs compared with age (P < .001). Women had greater mean CSF F2-IsoP concentrations than men at all ages after adjusting for other factors (P = .02). Neither the concentration of CSF Alzheimer disease biomarkers nor inheritance of the APOE ε4 allele was associated with the CSF F2-IsoP concentration in this group of medically healthy, cognitively normal adults (P > .05). The association between CSF F2-IsoP concentrations and race was not significant after controlling for the effect of current smoking status (P = .45)., Conclusions and Relevance: Our results are consistent with an age-related increase in free radical injury in the human brain and uniquely suggest that this form of injury may be greater in women than in men. Our results also highlighted 2 lifestyle modifications (ie, body mass index and smoking) that would have an even greater effect on suppressing free radical injury to the brain than would suppressing the processes of aging. These results inform efforts to achieve success in the Healthy Brain Initiative 2013-2018.

Aims: We prospectively examined the relationship between site-specific peak plantar pressure (PPP) and ulcer risk. Researchers have previously reported associations between diabetic foot ulcer and elevated plantar foot pressure, but the effect of location-specific pressures has not been studied., Methods: Diabetic subjects (n=591) were enrolled from a single VA hospital. Five measurements of in-shoe plantar pressure were collected using F-Scan. Pressures were measured at 8 areas: heel, lateral midfoot, medial midfoot, first metatarsal, second through fourth metatarsal, fifth metatarsal, hallux, and other toes. The relationship between incident plantar foot ulcer and PPP or pressure-time integral (PTI) was assessed using Cox regression., Results: During follow-up (2.4years), 47 subjects developed plantar ulcers (10 heel, 12 metatarsal, 19 hallux, 6 other). Overall mean PPP was higher for ulcer subjects (219 vs. 194kPa), but the relationship differed by site (the metatarsals with ulcers had higher pressure, while the opposite was true for the hallux and heel). A statistical analysis was not performed on the means, but hazard ratios from a Cox survival analysis were nonsignificant for PPP across all sites and when adjusted for location. However, when the metatarsals were considered separately, higher baseline PPP was significantly associated with greater ulcer risk; at other sites, this relationship was nonsignificant. Hazard ratios for all PTI data were nonsignificant., Conclusions: Location must be considered when assessing the relationship between PPP and plantar ulceration., (© 2013.)

Background: This study investigates the association between TOMM40 poly-T length, age at onset, and neuropathology in individuals with Alzheimer's disease (AD) with the apolipoprotein E (APOE) ε3/ε3 allele., Methods: Thirty-two presenilin 1 (PSEN1) mutation carriers with AD, 27 presenilin 2 (PSEN2) mutation carriers with AD, 59 participants with late-onset AD (LOAD), and 168 autopsied subjects from a community-based cohort were genotyped for TOMM40 intron 6 poly-T (rs10524523) length using short tandem repeat assays., Results: Among AD individuals with PSEN2 mutations, the presence of a long poly-T was associated with an earlier age at onset, whereas there were no such associations for subjects with PSEN1 mutations or LOAD. In community-based participants, the presence of a long poly-T was associated with increased neuritic tangles and a greater likelihood of pathologically diagnosed AD., Conclusion: TOMM40 intron 6 poly-T length may explain some of the variation in age at onset in PSEN2 familial AD and may be associated with AD neuropathology in persons with APOE ε3/ε3., (Copyright © 2013 The Alzheimer's Association. All rights reserved.)

Studies of traumatic brain injury from all causes have found evidence of chronic hypopituitarism, defined by deficient production of one or more pituitary hormones at least 1 year after injury, in 25-50% of cases. Most studies found the occurrence of posttraumatic hypopituitarism (PTHP) to be unrelated to injury severity. Growth hormone deficiency (GHD) and hypogonadism were reported most frequently. Hypopituitarism, and in particular adult GHD, is associated with symptoms that resemble those of PTSD, including fatigue, anxiety, depression, irritability, insomnia, sexual dysfunction, cognitive deficiencies, and decreased quality of life. However, the prevalence of PTHP after blast-related mild TBI (mTBI), an extremely common injury in modern military operations, has not been characterized. We measured concentrations of 12 pituitary and target-organ hormones in two groups of male US Veterans of combat in Iraq or Afghanistan. One group consisted of participants with blast-related mTBI whose last blast exposure was at least 1 year prior to the study. The other consisted of Veterans with similar military deployment histories but without blast exposure. Eleven of 26, or 42% of participants with blast concussions were found to have abnormal hormone levels in one or more pituitary axes, a prevalence similar to that found in other forms of TBI. Five members of the mTBI group were found with markedly low age-adjusted insulin-like growth factor-I (IGF-I) levels indicative of probable GHD, and three had testosterone and gonadotropin concentrations consistent with hypogonadism. If symptoms characteristic of both PTHP and PTSD can be linked to pituitary dysfunction, they may be amenable to treatment with hormone replacement. Routine screening for chronic hypopituitarism after blast concussion shows promise for appropriately directing diagnostic and therapeutic decisions that otherwise may remain unconsidered and for markedly facilitating recovery and rehabilitation.

Context: Late-life depression is associated with increased risk of dementia, but the temporal relationship between depression and development of dementia remains unclear., Objectives: To examine the association between risk of dementia and baseline depressive symptoms; history of depression, particularly early-life (<50 years) vs late-life depression (≥50 years); and individual domains of the Center for Epidemiologic Studies Depression Scale., Design: A large cohort with initially nondemented participants was followed up biennially for up to 15 years. Baseline depressive symptoms were assessed using the 11-item version of the Center for Epidemiologic Studies Depression Scale; presence of significant depressive symptoms was defined as a score of 11 or greater. Self-reported history of depression was collected at the baseline interview. Cox proportional hazards regression was used to assess the association between depression and dementia risk., Setting: Population-based cohort drawn from members of the Group Health Cooperative in Seattle, Washington., Participants: A cohort of 3410 participants without dementia aged at least 65 years., Results: During a mean of 7.1 years of follow-up, 658 participants (19.3%) developed dementia. At baseline, 9.4% of participants had presence of significant depressive symptoms, and 21.2% reported a history of depression. The adjusted hazard ratio for dementia associated with baseline depressive symptoms was 1.71 (95% confidence interval, 1.37-2.13), after adjusting for age at entry, sex, educational level, and wave of enrollment. Compared with participants without depression history, those with late-life depression were at increased dementia risk (adjusted hazard ratio, 1.46; 95% confidence interval, 1.16-1.84), but early-life depression had no association with dementia risk (1.10 [0.83-1.47]). Depressed mood (adjusted hazard ratio, 1.48; 95% confidence interval, 1.25-1.76) and perceived performance difficulty (1.39 [1.15-1.67]) were independently associated with dementia., Conclusion: This study confirmed that late-life depression is associated with increased risk of dementia and supplied evidence that late-life depression may be an early manifestation of dementia rather than increasing risk for dementia.

Lower limb amputees have decreased balance during daily ambulation compared to nonamputees. An optimally compliant torsion adapter, which enables transverse plane rotation at the socket-pylon junction may reduce limb asymmetries and improve comfort leading to increased confidence and stability during gait. The purpose of this study was to determine if the presence of a torsion adapter affects amputee sensitivity to local perturbations (local dynamic stability) during straight-line walking and during a turning task. Ten unilateral transtibial amputees were fit with a torsion and rigid adapter in random order and blinded to the condition. After a 3-week acclimation period, kinematic data were collected while subjects walked in a straight-line on a treadmill and around a 1-m radius circular path at constant speed. Maximum finite-time Lyapunov exponents (λ), an estimator of local dynamic stability, were calculated for the amputee's sagittal plane hip, knee and ankle angles for each condition. The prosthetic limb λ was greater during a turn compared to straight-line walking, suggesting amputees are less stable while turning. There were no statistically significant differences found in λ between adapters during both walking conditions, suggesting the torsion adapter had no effect on amputee stability; however, high inter-subject variability due to the examined population and turning task may have masked a small decrease in prosthetic limb hip and knee stability for the torsion adapter during straight-line gait. Therefore, the torsion adapter's added degree of freedom may have a small adverse effect on prosthetic limb stability during straight-line walking and no effect on turning., (Published by Elsevier Ltd.)

Objectives: To determine whether risk reduction of statins for Alzheimer's disease (AD) varies by age or presence of apolipoprotein E (APOE) epsilon4 allele., Design: A cohort of cognitively intact elderly participants was assessed biennially for dementia and AD., Setting: Community based., Participants: Three thousand three hundred ninety-two members of a health maintenance organization (HMO) aged 65 and older and without dementia., Measurements: Statin use was identified from the HMO pharmacy database, and proportional hazards models were applied with statin use as a time-dependent covariate to assess the association between statins and AD and the modifying effects of age and the APOE epsilon4 allele., Results: Over an average of 6.1 years of follow-up of 3,099 participants, 263 participants developed probable AD. The adjusted hazard ratio (aHR) for statin use was 0.62 (95% confidence interval (CI)=0.40-0.97) for AD in models including demographic characteristics and vascular risk factors as covariates. The strength of the association between statins and AD diminished with age (statin-by-age at entry interaction P=.04); the aHR in those younger than 80 was 0.44 (95% CI=0.25-0.78), versus 1.22 (95% CI=0.61-2.42) for aged 80 and older. The interaction term for statin use-by-APOE epsilon4 was not significant (P=.65)., Conclusion: This enlarged study confirms earlier findings that statin therapy in early old age, but not in late age, may be associated with a lower risk of AD. The relationship between statin use and AD was consistent across APOE genotypes.

Cigarette smoking has been associated repeatedly in observational studies with decreased risk of Parkinson's disease (PD), but its relationship to the risk of dementia or Alzheimer's disease (AD) is inconsistent. All of these studies have used clinical diagnoses of disease. We tested the hypothesis that lifetime cigarette use might be associated with reduced risk of neuropathologic changes of Lewy-related pathology (LRP) in multiple brain regions or with reduced risk of consensus neuropathologic changes of AD in a prospective community-based study of brain aging and dementia, the Adult Changes in Thought (ACT) study. We observed that heavy lifetime cigarette smoking (>50 pack years) was associated with significantly reduced relative risk (RR) for LRP, but not AD-type pathologic changes, after correcting for selection bias, and with significantly reduced frequency of LRP in the substantia nigra. These findings are the first of which we are aware to associate reduced LRP in human brain with any exposure, and substantiate observational studies that have associated cigarette smoking with reduced risk of PD. Although cigarette smoking is too toxic to suggest as a treatment, if confirmed, these findings may guide future therapeutic strategies that attempt to suppress LRP in human brain by other means.

Objective: Patients with chronic obstructive pulmonary disease (COPD) and comorbid mental disorders are known to have worse health status. The association between these variables remains complex and poorly understood. We sought to better understand the association between COPD severity, mental disorders (depression/anxiety), and health status., Method: This cross-sectional study compared participants without COPD or with mild COPD (n = 162) to those with moderate (n = 25), severe (n = 38), and very severe (n = 26) COPD. We recruited participants from a primary care and a pulmonary clinic at a veterans affairs medical center between July 2001 until September 2002. We used the Patient Health Questionnaire to screen for depression and anxiety and the Posttraumatic Stress Disorder Checklist to screen for posttraumatic stress disorder. Health status was assessed with the veteran's version of the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and the Shortness of Breath Questionnaire (SOBQ)., Results: COPD severity was associated with worse physical status and dyspnea as measured by the SF-36 physical component summary and the SOBQ but was not associated with worse mental status as measured by the SF-36 mental component summary. At each level of COPD severity, participants with mental disorders had worse health status and dyspnea as measured by the SF-36 physical component summary, mental component summary, and SOBQ. Significant linear trends with COPD severity were associated with increased prevalence of any depressive disorder, major depressive disorder, and nonpanic/non-PTSD anxiety disorders (all tests for linear trend, P < .01)., Conclusions: Independent of COPD severity, comorbid mental disorders were associated with worse health status and dyspnea. Studies are needed to determine whether patients with comorbid mental disorders may have more significant improvement in physical symptoms and functioning if providers focus more on psychiatric conditions.

Objectives: To examine correlations between blood pressure (BP) and dementia-related pathological brain changes in a community-based autopsy sample., Design: Prospective cohort study., Setting: A large health maintenance organization in Seattle, Washington., Participants: A cohort of 250 participants aged 65 and older and cognitively normal at time of enrollment in the Adult Changes in Thought (ACT) Study and who underwent autopsy., Measurements: BP and history of antihypertensive treatment were taken at enrollment. A linear regression model was used to examine the relationship between BP (systolic (SBP) and diastolic (DBP)) at enrollment and pathological changes in the cerebrum (cystic macroscopic infarcts, microinfarcts, neuritic plaques, neurofibrillary tangles, and cortical Lewy bodies)., Results: The presence of more than 2 microinfarcts, but not any other pathological change, was independently associated with SBP in younger participants (65-80, n=137) but not in older participants (>80, n=91). The relative risk (RR) for more than two microinfarcts with each 10-mmHg increase in SBP was 1.15 (95% confidence interval (CI)=1.00-1.33) in the younger participants, adjusted for age at entry, sex, and time to death. This RR was particularly strong in younger participants not taking antihypertensive medications (RR=1.48, 95% CI=1.21, 1.81); significant associations were not observed in participants treated for hypertension. Findings for DBP were negative., Conclusion: The association between high SBP and cerebrovascular damage in untreated older adults (65-80) suggests that adequate hypertension treatment may reduce dementia risk by minimizing microvascular injury to cerebrum.

Objective: Cardiac output and sFlt-1 are elevated prior to clinical evidence of preeclampsia. Early treatment of high cardiac output with atenolol decreases the risk for preeclampsia. We hypothesized that atenolol would impact circulating sFlt-1., Methods: Cardiac output and plasma sFlt-1 were measured

Aims: We assessed baseline clinical foot shape for 2939 feet of diabetic subjects who were monitored prospectively for foot ulceration., Methods: Assessments included hammer/claw toes, hallux valgus, hallux limitus, prominent metatarsal heads, bony prominences, Charcot deformity, plantar callus, foot type, muscle atrophy, ankle and hallux mobility, and neuropathy. Risk factors were linked to ulcer occurrence and location via a Cox proportional hazards model., Results: Hammer/claw toes (hazard ratio [HR] (95% confidence interval [CI])=1.43 (1.06, 1.94) p=0.02), marked hammer/claw toes (HR=1.77 (1.18, 2.66) p=0.006), bony prominences (HR=1.38 (1.02, 1.88), p=0.04), and foot type (Charcot or drop foot vs. neutrally aligned) (HR=2.34 (1.33, 4.10), p=0.003) were significant risk factors for ulceration adjusting for age, body mass index, insulin medication, ulcer history and amputation history. With adjustment for neuropathy only hammer/claw toes (HR=1.40 (1.03, 1.90), p=0.03) and foot type (HR=1.76 (1.04, 3.04), p=0.05) were significantly related to ulceration. However, there was no relationship between ulcer location and foot deformity., Conclusions: Certain foot deformities were predictive of ulceration, although there was no relationship between clinical foot deformity and ulcer location.

Successful community and household ambulation require the ability to navigate corners and maneuver around obstacles, posing unique challenges compared to straight-line walking. The challenges associated with turning may contribute to an increased incidence of falling and the occurrence of fall-related injuries. A measure of stability applied to turning gait may be able to quantify a system's response to naturally occurring disturbances associated with turning and identify subjects at greater risk of falling. An index of stability has been used previously to assess the rate of kinematic separation (local dynamic stability) during straight-line gait. The purpose of this study was to determine if local dynamic stability during constant speed turning is reduced compared to straight-line treadmill walking. Maximum finite-time Lyapunov exponents (lambda) were used to estimate the local stability of able-bodied subjects' (n=19) sagittal plane hip, knee, and ankle trajectories for turning compared to straight-line walking at two different walking speeds. Turning lambda was greater than straight lambda for the hip, right knee, and ankle (p<0.05). Turning lambda for the left knee angle was similar to straight lambda. There were no differences in lambda between left and right limbs for the hip and ankle and also no differences between the inside and outside limbs during turning for all joints. These findings indicate able-bodied subjects' hip, right knee, and ankle kinematics are less locally stable while turning than walking in a straight line and may be used as a comparative tool for determining the efficacy of therapeutic interventions for mobility-impaired populations.

Background: Treatment with 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors ("statins") has been associated in some epidemiologic studies with reduced risk of Alzheimer disease (AD). However, direct evidence of statin effects on neuropathologic markers of AD is lacking. We investigated whether antecedent statin exposure is associated with neuritic plaque (NP) or neurofibrillary tangle (NFT) burden in a population-based sample of human subjects., Methods: Brain autopsies were performed on 110 subjects, ages 65 to 79 years, who were cognitively normal at enrollment into the Adult Changes in Thought Study. Neuropathologic findings were compared between statin users with > or =3 prescriptions of > or =15 pills of simvastatin, pravastatin, lovastatin, or atorvastatin vs nonusers, based on pharmacy dispensing records., Results: After controlling for age at death, gender, cognitive function at study entry, brain weight, and presence of cerebral microvascular lesions, the odds ratio (OR) for each unit increase in Braak NFT stage in statin users vs nonusers was 0.44 (95% CI: 0.20 to 0.95). The OR for each unit increase in Consortium to Establish a Registry for Alzheimer's Disease (CERAD) staging of NPs did not deviate significantly from unity (OR 0.69; 95% CI: 0.32 to 1.52). However, the risk for typical AD pathology (Braak stage > or = IV and CERAD rating > or = moderate) was reduced in statin users (OR 0.20; 95% CI: 0.05 to 0.86)., Conclusions: These findings demonstrate an association between antecedent statin use and neurofibrillary tangle burden at autopsy. Additional study is needed to examine whether statin use may be causally related to decreased development of Alzheimer disease-related neuropathologic changes.

Objectives: To assess variation in the association between blood pressure (BP) and risk for dementia across a spectrum of older ages and to examine BP changes before dementia onset., Design: Prospective cohort study., Setting: A large health maintenance organization in Seattle, Washington., Participants: A cohort of 2,356 members of a large health maintenance organization aged 65 and older who were initially without dementia., Measurements: Dementia diagnosis was assessed biennially, and systolic (SBP) and diastolic BP (DBP) were measured at baseline and at four follow-up assessments. Cox proportional hazards models were used to estimate hazard ratios (HRs) for dementia and Alzheimer's disease (AD) associated with baseline BP in different age groups., Results: Within the youngest age group (65-74 at enrollment) a greater risk for dementia was found in participants with high SBP (> or = 160 mmHg) (hazard ratio (HR) = 1.60, 95% confidence interval (CI) = 1.01-2.55) or borderline-high DBP (80-89 mmHg) (HR = 1.59, 95% CI = 1.07-2.35) than for those with normal BP (SBP < 140 mmHg and DBP < 80 mmHg). The dementia risk associated with SBP declined with increasing age (SBP-by-age interaction, P=.01). SBP declined similarly with aging in subjects who developed dementia and those who did not. Thus, in this sample, the association between SBP and dementia risk was not dependent on when BP was measured in relation to onset of dementia., Conclusion: High SBP was associated with greater risk of dementia in the young elderly (< 75) but not in older subjects. Adequate control of hypertension in early old age may reduce the risk for dementia.

Objective: We developed assays for measurement of urinary betaLH and betaFSH under collection and storage conditions typical of non-clinical research settings., Design and Methods: IEMAs for free betaLH and total betaFSH were validated by standard methods. Stability of urinary betaLH and betaFSH was tested across freeze-thaws and stored long term at 4 degrees C or -20 degrees C, or short term at room temperature, and with heating to dissociate the subunits., Results: The IEMAs exhibited acceptable parallelism, specificity, recovery (averaging 100% for betaLH, 97% for betaFSH), imprecision (maximum within-run and between run CVs, respectively, 4.8% and 25.7% for betaLH, 5.6% and 17.0% for betaFSH), and minimum detectable dose (2.5 pmol/L for betaLH, 6.8 pmol/L for betaFSH). Urine and serum measures were highly correlated (r=0.95 for LH, 0.86 for FSH). There was no consistent decline with any storage type. Dissociation of subunits by heating was needed for betaLH, but not betaFSH., Conclusion: These IEMAs measure free betaLH and total betaFSH, overcoming inter-individual variability in, and collection and storage effects on, subunit dissociation, without the need for urine preservatives.

Objective: We sought to determine whether a history of gestational diabetes mellitus (GDM) further increases the risk of cardiovascular disease (CVD) in parous women with first-degree relatives with type 2 diabetes., Research Design and Methods: Women with (n = 332) and without (n = 663) a history of GDM were compared regarding 1) the revised National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome criteria, 2) the prevalence of type 2 diabetes, and 3) self-reported CVD., Results: Women with prior GDM were younger (48.6 +/- 0.7 vs. 52.4 +/- 0.6 years [means +/- SE];P < 0.001) and less likely to be postmenopausal (48.3 vs. 57.9%; P < 0.005). Although both groups were obese (BMI 34.4 +/- 1.2 vs. 33.7 +/- 0.6 kg/m(2)), women with prior GDM were more likely to have metabolic syndrome (86.6 vs. 73.5%; P < 0.001) and type 2 diabetes (93.4 vs. 63.3%; P < 0.001). Moreover, they had a higher prevalence of CVD (15.5 vs. 12.4%; adjusted odds ratio 1.85 [95% CI 1.21-2.82];P = 0.005) that occurred at a younger age (45.5 +/- 2.2 vs. 52.5 +/- 1.9 years;P = 0.02) and was independent of metabolic syndrome (1.74 [1.10-2.76]; P = 0.02) and type 2 diabetes (1.56 [1.002-2.43];P < 0.05)., Conclusions: Among women with a family history of type 2 diabetes, those with prior GDM were even more likely to not only have CVD risk factors, including metabolic syndrome and type 2 diabetes, but also to have experienced CVD events, which occurred at a younger age. Thus, women with both a family history of type 2 diabetes and personal history of GDM may be especially suitable for early interventions aimed at preventing or reducing their risk of CVD and diabetes.

Background: We evaluate the performance of ovulation detection methods and present new approaches, including evaluation of methods for precision, combining multiple markers into a hierarchical system and using ovulation markers in intermittent sampling designs., Methods: With serum LH peak day as the 'gold standard' of ovulation, we estimated accuracy and precision of ovulation day algorithms using 30 ovulatory menstrual cycles with daily urinary and serum hormones and transvaginal ultrasound. Sensitivity and specificity for estimating the presence of ovulation were tested using visually assessed ovulatory (30) and anovulatory (22) cycles., Results: Sensitivity and specificity ranged from 70 to 100% for estimating presence of ovulation with twice-per-cycle, weekly, twice weekly, every-other-day and daily specimens. A combined hierarchical method estimated ovulation day using daily specimens within +/-2 days of the gold standard in 93% of cases. Accuracy of estimating ovulation day within +/-2 days using intermittent sampling ranged from 40% (weekly sampling) to 97% (every-other-day)., Conclusions: A combined hierarchical algorithm using precise and accurate markers allows maximal use of available data for efficient and objective identification of ovulation using daily specimens. In intermittent sampling designs, the presence and the timing of ovulation can be estimated with good sensitivity, specificity and accuracy.

Objective: To determine whether the hyperbolic relationship between insulin sensitivity and the acute insulin response to glucose (AIRg) exists in subjects with impaired fasting glucose (IFG) or decreased glucose tolerance., Research Design and Methods: We studied 219 healthy subjects (88 male and 131 female subjects, aged 26-75 years) with fasting plasma glucose (FPG) <6.11 mmol/l. Subjects underwent an intravenous glucose tolerance test to determine the insulin sensitivity index (Si), AIRg, and the glucose disappearance constant (Kg), the latter a measure of intravenous glucose tolerance., Results: Si and AIRg were inversely related for the entire cohort, and this relationship was not significantly different from hyperbolic. The inverse relationship between Si and AIRg was not significantly different when compared between groups based on fasting glucose (normal fasting glucose [NFG], FPG <5.56 mmol/l vs. IFG, FPG 5.56-6.11 mmol/l) or by the Kg quartile. However, the curve relating Si and AIRg was left shifted in the IFG compared with NFG group (P < 0.001) and was progressively more left shifted with decreasing Kg (P < 0.001), consistent with decreasing beta-cell function. These changes were not observed for the curves relating Si and fasting insulin, suggesting that in the fasting state beta-cell function is maintained even in patients with mild IFG. Finally, the disposition index (DI) (Si x AIRg) was calculated as a measure of beta-cell function. The DI progressively decreased with increasing FPG, even in the group of subjects classified as NFG., Conclusions: The inverse relationship between insulin sensitivity and AIRg is consistent with a hyperbola not only in subjects with normal glucose tolerance but also with mild IFG or decreased Kg. Based on a hyperbolic relationship, a decrease in beta-cell function can be detected as FPG increases, even in patients who are normal glucose tolerant.