Randomized controlled pilot trial of prazosin for prophylaxis of posttraumatic headaches in active-duty service members and veterans.

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.

Performance of a condensed protocol to assess limbic-predominant age-related TDP-43 encephalopathy neuropathologic change.

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 effect of diabetes and tissue depth on adipose chamber size and plantar soft tissue features.

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 µm2 vs 14,157 ± 1153 µm2), 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 µm2 vs 16627 ± 130 µm2, 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.

Correlates of Conversion from Mild Cognitive Impairment to Dementia with Lewy Bodies: Data from the National Alzheimer's Coordinating Center.

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.

Self-perceived irritability among OEF/OIF/OND veterans with a history of deployment-related mTBI: Associations with prospective memory and quality of life.

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.

The Impact of Coronal Plane Deformity on Ankle Arthrodesis and Arthroplasty.

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.

Comparing 4-Year Changes in Patient-Reported Outcomes Following Ankle Arthroplasty and Arthrodesis.

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.

Ankle fusion and replacement gait similar post-surgery, but still exhibit differences versus controls regardless of footwear.

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.

The effect of prosthetic foot stiffness on foot-ankle biomechanics and relative foot stiffness perception in people with transtibial amputation.

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.

Neuropathy, claw toes, intrinsic muscle volume, and plantar aponeurosis thickness in diabetic feet.

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 (R2 = 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.

Effectiveness and Safety of Ankle Arthrodesis Versus Arthroplasty: A Prospective Multicenter Study.

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.

Step Activity After Surgical Treatment of Ankle Arthritis.

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.

Variables associated with subjective cognitive change among Iraq and Afghanistan war Veterans with blast-related mild traumatic brain injury.

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 (MAge = 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.

Cognitive Self-Efficacy and Mental Health Ratings after a Memory Skills Group for Older Veterans with PTSD.

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.

Frequency and Impact of Adverse Events in Patients Undergoing Surgery for End-Stage Ankle Arthritis.

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.

Associations between CSF cortisol and CSF norepinephrine in cognitively normal controls and patients with amnestic MCI and AD dementia.

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.

Comparison of Treatment Outcomes of Arthrodesis and Two Generations of Ankle Replacement Implants.

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.

Histomorphological and biochemical properties of plantar soft tissue in diabetes.

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.

Cognitive Trajectory Changes Over 20 Years Before Dementia Diagnosis: A Large Cohort Study.

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.

Cerebrospinal fluid biomarkers for Alzheimer's and vascular disease vary by age, gender, and APOE genotype in cognitively normal adults.

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 beta1-42 (Aß42), phospho-tau-181 (p-tau181), 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-tau181 increased with age over the adult life span (p < 0.01) with no gender differences in those increases. CSF Aß42 concentration varied according to age, gender, and APOE genotype (interaction of age × gender × Îµ4, 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.