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Preclinical and epidemiologic studies suggest a protective effect of statins on Alzheimer disease (AD). Experimental evidence indicates that some statins can cross the blood-brain barrier, alter brain cholesterol metabolism, and may ultimately decrease the production of amyloid-beta (Abeta) peptide. Despite these promising leads, clinical trials have yielded inconsistent results regarding the benefits of statin treatment in AD. Seeking to detect a biological signal of statins effect on AD, we conducted a 12-week open-label trial with simvastatin 40 mg/d and then 80 mg/d in 12 patients with AD or amnestic mild cognitive impairment and hypercholesterolemia. We quantified cholesterol precursors and metabolites and AD biomarkers of Abeta and tau in both plasma and cerebrospinal fluid at baseline and after the 12-week treatment period. We found a modest but significant inhibition of brain cholesterol biosynthesis after simvastatin treatment, as indexed by a decrease of cerebrospinal fluid lathosterol and plasma 24S-hydroxycholesterol. Despite this effect, there were no changes in AD biomarkers. Our findings indicate that simvastatin treatment can affect brain cholesterol metabolism within 12 weeks, but did not alter molecular indices of AD pathology during this short-term treatment. [ABSTRACT FROM AUTHOR]

Objective: To compare the real-world clinical effectiveness and long-term clinical trajectory in patients with Alzheimer disease (AD) treated with combination (COMBO) therapy consisting of cholinesterase-inhibitor (CI) plus memantine (MEM) versus CI alone versus no treatment with either.Methods: Three hundred eighty-two subjects with probable AD underwent serial clinical evaluations at a memory disorders unit. Cognition was assessed by the Information-Memory-Concentration subscale of the Blessed Dementia Scale (BDS) and function was assessed by the Weintraub Activities of Daily Living Scale (ADL) at 6-month intervals. One hundred forty-four subjects received standard care without CI or MEM (NO-RX), 122 received CI monotherapy, and 116 received COMBO therapy with CI plus MEM. Mean follow-up was 30 months (4.1 visits) and mean cumulative medication treatment time was 22.5 months. Rates of decline were analyzed using mixed-effects regression models, and Cohen's d effect sizes were calculated annually for years 1 to 4.Results: Covarying for baseline scores, age, education, and duration of illness, the COMBO group had significantly lower mean annualized rates of deterioration in BDS and ADL scores compared with the CI (P<0.001; Cohen's dBDS=0.10-0.34 and dADL=0.23-0.46 at 1 to 2 y) and NO-RX groups (P<0.001; Cohen's dBDS=0.56-0.73 and dADL=0.32-0.48 at 1 to 2 y). For the COMBO group, Cohen's d effect sizes increased with treatment duration. Similar comparisons significantly favored the CI over the NO-RX group on the BDS.Conclusions: COMBO therapy slows cognitive and functional decline in AD compared with CI monotherapy and no treatment. These benefits had small-to-medium effect sizes that increased with time on treatment and were sustained for years. [ABSTRACT FROM AUTHOR]

Late-onset epilepsy has been linked with accelerated cognitive decline and a higher risk of dementia. In this study, we sought to characterize the cognitive profile of participants with late-onset unexplained epilepsy and compare their MRI findings to healthy controls, to better understand underlying disease mechanisms. We recruited participants with at least one new-onset unexplained seizure at age 55 or later, without cortical lesions on MRI, within 5 years of the first seizure. We administered a neuropsychological battery to generate Preclinical Alzheimer Cognitive Composite and composite scores for delayed verbal recall, processing speed and executive function. We held a consensus meeting to determine whether the participants fulfilled criteria for mild cognitive impairment. An MRI volumetric analysis of hippocampal, amygdalae, and white matter hyperintensity volume was performed and compared to 353 healthy controls from the Harvard Aging Brain Study. On late-onset unexplained epilepsy participants, we also obtained 24-h EEG recording. Seventy participants were recruited, mean age 71.0 ± 7.0 years, 49% female, 15.6 ± 3.0 years of education. Impaired cognition ( z -score ≤ -1.5) for late-onset unexplained epilepsy included the following: 15.9% for Preclinical Alzheimer Cognitive Composite -5, 23.2% for delayed verbal recall, 15.6% for processing speed and 7.5% for executive function. Seventeen percent were found to have mild cognitive impairment. Late-onset unexplained epilepsy participants who were drug resistant were more likely to have cognitive impairment (50% vs. 9%). When controlling for age, sex and race, late-onset unexplained epilepsy group had lower left AV (%; β = -0.003, P = 0.0016), right AV (%) (β = -0.003, P = 0.01), and log-transformed WMV (mm 3 ; β = -0.21, P = 0.03) compared with Harvard Aging Brain Study (HABS); there were no differences in left or right HV between groups. EEG captured epileptiform abnormalities in 49% late-onset unexplained epilepsy participants, with a left temporal predominance (54%). In this single-site study of prospectively enrolled participants with late-onset unexplained epilepsy, we show that individuals with late-onset unexplained epilepsy exhibit cognitive impairments, mostly in verbal memory, and temporal dysfunction with left-sided predominance. Neuroimaging, when compared with healthy controls, shows lower amygdalae and white matter hyperintensity but not hippocampal volumes suggesting that the amygdalae is one of the earliest sites involved in the disease. The results also highlight the importance of seizure control given the association between mild cognitive impairment and drug-resistant epilepsy. Future studies extending these findings to Alzheimer's disease biomarkers and longitudinal follow-up will inform predictors of cognitive decline., Competing Interests: A.D.L. received grants from Sage Therapeutics; and has served as a consultant for Acadia Therapeutics and Neurona Therapeutics. The remaining authors have no competing interests., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: There is increasing interest in the development of scalable digital mental health interventions for perinatal populations to increase accessibility. Mobile behavioral activation (BA) is efficacious for the treatment of perinatal depression; however, the effect of comorbid anxiety and depression (CAD) on symptom trajectories remains underexplored. This is important given that at least 10% of women in the perinatal period experience CAD., Objective: We assessed whether there were differences in symptom trajectories in pregnant participants with CAD as compared to those with depression only (ie, major depressive disorder [MDD]) during intervention with a BA mobile gaming app., Methods: Pregnant adults with either CAD (n=10) or MDD (n=7) used a BA app for 10 weeks and completed biweekly symptom severity questionnaires for depression and anxiety. We assessed whether baseline diagnoses were associated with differential symptom trajectories across the study with mixed effects longitudinal models., Results: When controlling for baseline symptoms, results revealed a significant interaction between baseline diagnosis and the quadratic component of study week on anxiety (β=.18, SE 0.07; t62=2.61; P=.01), revealing a tendency for anxiety in the CAD group to increase initially and then decrease at an accelerated rate, whereas MDD symptoms were relatively stable across time. There was a significant effect of linear time on depression (β=-.39, SE 0.11; t68=-3.51; P=.001), showing that depression declined steadily across time for both groups. There was a significant effect of baseline diagnosis on depression (β=-8.53, SE 3.93; t13=-2.17; P=.05), suggesting that those with MDD had higher follow-up depression compared to those with CAD when holding other predictors constant., Conclusions: The app was beneficial in reducing depression symptoms in perinatal individuals with different comorbidity profiles. With respect to anxiety symptom trajectories, however, there was more variability. The app may be especially effective for the treatment of anxiety symptoms among individuals with CAD, as it encourages in-the-moment ecologically relevant exposure to anxiety-provoking stimuli. Despite no significant group difference in baseline anxiety symptoms, the MDD group did not have a significant reduction in their anxiety symptoms across the study period, and some individuals had an increase in anxiety. Findings may point to opportunities for the augmentation of BA gaming apps for those with MDD to more effectively target anxiety symptoms. Overall, findings suggest there may be value in considering comorbidities and individual variations in participants when developing scalable mobile interventions for perinatal populations., (© Gabriella E Hamlett, Chloe Schrader, Craig Ferguson, Lauren A Kobylski, Rosalind Picard, Joseph J Locascio, Richard J McNally, Lee S Cohen, Rachel Vanderkruik. Originally published in JMIR Formative Research (https://formative.jmir.org).)

Background: Nerve xenografts harvested from transgenic α1,3-galactosyltransferase knockout pigs lack the epitope responsible for hyperacute rejection in pig-to-primate transplants. It is unknown whether these cold-preserved nerve grafts support axonal regeneration in another species during and after immunosuppression. The authors compared outcomes between autografts and cold-preserved xenografts in a rat sciatic model of nerve gap repair., Methods: Fifty male Lewis rats had a 1-cm sciatic nerve defect repaired using autograft and suture ( n = 10); 1-week or 4-week cold-preserved xenograft and suture ( n = 10 per group); or 1-week or 4-week cold-preserved xenograft and photochemical tissue bonding using a human amnion wrap ( n = 10 per group). Rats with xenografts were given tacrolimus until 4 months postoperatively. At 4 and 7 months, rats were killed and nerve sections were harvested. Monthly sciatic functional index (SFI) scores were calculated., Results: All groups showed increases in SFI scores by 4 and 7 months. The autograft suture group had the highest axon density at 4 and 7 months. The largest decrease in axon density from 4 to 7 months was in the group with 1-week cold-preserved photochemical tissue bonding using a human amnion wrap. The only significant difference between group SFI scores occurred at 5 months, when both 1-week cold-preserved groups had significantly lower scores than the 4-week cold-preserved suture group., Conclusions: The results suggest that α1,3-galactosyltransferase knockout nerve xenografts may be viable alternatives to autografts. Further studies of long-gap repair and comparison with acellular nerve allografts are needed., Clinical Relevance Statement: This proof-of-concept study in the rat sciatic model demonstrates that cold-preserved α1,3-galactosyltransferase knockout porcine xenografts support axonal regeneration and viability following immunosuppression withdrawal. These results further suggest a role for both cold preservation and photochemical tissue bonding in modulating the immunological response at the nerve repair site., (Copyright © 2024 by the American Society of Plastic Surgeons.)

The COVID-19 pandemic and subsequent social distancing guidelines and restrictions brought on changes in the everyday experiences of older adults. It is not clear, however, to what extent the pandemic has impacted the importance of everyday preferences for persons with cognitive impairment (CI) or the proxy ratings of those preferences. The sample of this study included 27 dyads of persons with CI and their care partners. The Preferences for Everyday Living Inventory was used to assess importance of preferences among persons with CI; care partners completed concurrent proxy assessments. Mixed random and fixed effects longitudinal models were used to evaluate changes in ratings and concordance levels between persons with CI and care partners prior to and during the COVID-19 pandemic. Persons with CI rated autonomous choice preferences as significantly more important during the COVID-19 pandemic than before; there was no association between the COVID-19 pandemic and change in other everyday preferences domains or discrepancy in proxy assessments of everyday preferences. Identifying avenues to support and provide for autonomy in the decision-making of older adults with CI may offer a way forward in mitigating the psychological and behavioral impacts of the COVID-19 pandemic in this population., (© The Author(s), 2023. Published by Cambridge University Press on behalf of International Psychogeriatric Association.)

We aimed at investigating the presence of patterns that account for the phenotypic variability in a myotonic dystrophy type 2 (DM2) retrospective cohort at the Mass General Brigham Neuromuscular Centers. We collected the presence or absence of 23 clinical variables at symptom onset and diagnosis (n = 67 patients) and follow-up (n = 37 patients). We first identified set/s of variables (factors or cluster/s) representative of the large research data pool at onset by performing factor analyses, then assigned each patient to the cluster for which they had the highest computed total factor score. Twelve variables grouped into two distinct clusters that, based on their variable content, we named as proximal myotonic myopathy (PROMM)-DM2 or non-PROMM-DM2. Patients assigned to non-PROMM-DM2 more frequently had clinical myotonia and positive family history, and less frequently multiorgan involvement. Most patients (67.2 %) remained assigned to same cluster during disease course and 11 non-PROMM eventually transitioned to PROMM-DM2. Dyslipidemia and early cataracts (both in PROMM-DM2 cluster) were the earliest extramuscular manifestations that occurred during disease course and they accounted for the conversion of up to 8 out of 11 non-PROMM to PROMM converters. Identification of phenotypically homogeneous patient subgroups may help investigating DM2 prognosis and disease biomarkers in future prospective studies., Competing Interests: Declaration of competing interest Dr. Paloma Gonzalez Perez: None that could inappropriately influence (bias) this work. Dr. Vincent Picher-Martel: None that could inappropriately influence (bias) this work. Dr. Joseph Locascio: None that could inappropriately influence (bias) this work. Dr. Kathy Chaung: None that could inappropriately influence (bias) this work. Dr. William David: None that could inappropriately influence (bias) this work. Dr. Anthony Amato: none that could inappropriately influence (bias) this work, (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Calciphylaxis patients historically have experienced diagnostic challenges and high morbidity; however limited data is available examining these characteristics over time., Objective: The primary goals were to a) investigate factors associated with diagnostic delay of calciphylaxis and b) assess morbidity outcomes. The secondary goal was to provide updated mortality rates., Methods: A retrospective review of 302 adult patients diagnosed with calciphylaxis between January 1, 2006 and December 31, 2022 was conducted. Univariate and multivariate statistical analyses were performed., Results: Nonnephrogenic calciphylaxis (P = .0004) and involvement of the fingers (P = .0001) were significantly associated with an increased diagnostic delay, whereas involvement of the arms (P = .01) and genitalia (P = .022) resulted in fewer days to diagnosis. Almost all patients with genitalia, finger, or toe involvement had nephrogenic disease. The number of complications per patient decreased with time, especially for wound infections (P = .028), increase in lesion number (P = .012), and recurrent hospitalizations (P = .020). Updated 1-year mortality rates were 36.70% and 30.77% for nephrogenic and nonnephrogenic calciphylaxis, respectively., Limitations: Limitations include the retrospective nature and data from a single institution., Conclusion: Diagnostic delay, particularly in nonnephrogenic calciphylaxis, and complications per patient decreased with time, highlighting the importance of continued awareness to expedite diagnosis. Mortality rates have continued to improve in recent years., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Low-income white older adults and those of color are at greater risk for depression but less likely to receive care. We evaluated the impact of a one-to-one peer support intervention compared to active control delivered by nonpeers for this population., Design: Mixed methods, single-blind randomized controlled trial., Setting: Community-based social service and aging organizations and geriatric primary care., Participants: Low-income white older adults and those of color 50+ with depression., Interventions: Peer Enhanced Depression Care and nonpeer, social interaction control., Measurements: Primary outcome was depression (PHQ-9). Data were collected at baseline, postinterventions, 3, 6, 9, and 12 months. Poststudy interviews were conducted with both groups., Results: Among 149 randomized participants, the mean age was 70, 84% were women, 52% Black and 41% White. Both groups experienced an average decrease of 3.7 (SE: 0.55, 95% CI: [-4.77, -2.63]) points in depression from baseline to postintervention and 2.56 (SE: 0.71, 95% CI: [-3.95, -1.17]) points from baseline to 12 months. Effect sizes at postintervention (Cohen's d = 0.81) and at 12-months (Cohen's d = 0.52) indicate large and medium effects, respectively. Both groups experienced decreases in loneliness and increases in adaptive coping and self-efficacy. Qualitative findings suggest the intervention group learned coping skills and experienced behavior change, whereas control group described a general positive experience., Conclusions: Peer support intervention was not superior to social interactions delivered by nonpeers. Divergent quantitative and qualitative results suggest the need for additional effectiveness trials of peer support interventions outside of pandemic conditions. Trial Registration ClinicalTrials.gov Identifier: NCT04319094., Competing Interests: DISCLOSURES Authors of this manuscript declare no conflicts of interest such as affiliations with or involvement in any organization or entity with any financial interest or nonfinancial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2024 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo., Methods: The study cohort included all mice enrolled and randomized in the SPAN trial (N=1789). Mice were subjected to 60-minute MCAo and followed for a month. Thirteen biological and procedural independent variables and 4 functional (weight loss and 4-point neuroscore on days 1 and 2, corner test on days 7 and 28, and mortality) and 3 tissue (day 2, magnetic resonance imaging infarct volumes and swelling; day 30, magnetic resonance imaging tissue loss) outcome variables were prospectively captured. Multivariable regression with stepwise elimination was used to identify the predictors and their effect sizes., Results: Older age, active circadian stage at MCAo, and thinner and longer filament silicone tips predicted higher mortality. Older age, larger body weight, longer anesthesia duration, and longer filament tips predicted worse neuroscores, while high-fat diet and blood flow monitoring predicted milder neuroscores. Older age and a high-fat diet predicted worse corner test performance. While shorter filament tips predicted more ipsiversive turning, longer filament tips appeared to predict contraversive turning. Age, sex, and weight interacted when predicting the infarct volume. Older age was associated with smaller infarcts on day 2 magnetic resonance imaging, especially in animals with larger body weights; this association was most conspicuous in females. High-fat diet also predicted smaller infarcts. In contrast, the use of cerebral blood flow monitoring and more severe cerebral blood flow drop during MCAo, longer anesthesia, and longer filament tips all predicted larger infarcts. Bivariate analyses among the dependent variables highlighted a disconnect between tissue and functional outcomes., Conclusions: Our analyses identified variables affecting endovascular filament MCAo outcome, an experimental stroke model used worldwide. Multiple regression refuted some commonly reported predictors and revealed previously unrecognized associations. Given the multicenter prospective design that represents a sampling of real-world conditions, the degree of heterogeneity mimicking clinical trials, the large number of predictors adjusted for in the multivariable model, and the large sample size, we think this is the most definitive analysis of the predictors of preclinical stroke outcome to date. Future multicenter experimental stroke trials should standardize or at least ensure a balanced representation of the biological and procedural variables identified herein as potential confounders., Competing Interests: P.D. Lyden reports compensation from the National Institutes of Health Clinical Center for other services, and compensation from Apex Innovations and EMD Serono for consultant services. C. Ayata reports compensation from Neurelis Inc for other services.

Objectives: To investigate intra-patient variability of iodine concentration (IC) between three different dual-energy CT (DECT) platforms and to test different normalization approaches., Methods: Forty-four patients who underwent portal venous phase abdominal DECT on a dual-source (dsDECT), a rapid kVp switching (rsDECT), and a dual-layer detector platform (dlDECT) during cancer follow-up were retrospectively included. IC in the liver, pancreas, and kidneys and different normalized ICs (NIC PV :portal vein; NIC AA :abdominal aorta; NIC ALL :overall iodine load) were compared between the three DECT scanners for each patient. A longitudinal mixed effects analysis was conducted to elucidate the effect of the scanner type, scan order, inter-scan time, and contrast media amount on normalized iodine concentration., Results: Variability of IC was highest in the liver (dsDECT vs. dlDECT 28.96 (14.28-46.87) %, dsDECT vs. rsDECT 29.08 (16.59-62.55) %, rsDECT vs. dlDECT 22.85 (7.52-33.49) %), and lowest in the kidneys (dsDECT vs. dlDECT 15.76 (7.03-26.1) %, dsDECT vs. rsDECT 15.67 (8.86-25.56) %, rsDECT vs. dlDECT 10.92 (4.92-22.79) %). NIC ALL yielded the best reduction of IC variability throughout all tissues and inter-scanner comparisons, yet did not reduce the variability between dsDECT vs. dlDECT and rsDECT, respectively, in the liver. The scanner type remained a significant determinant for NIC ALL in the pancreas and the liver (F-values, 12.26 and 23.78; both, p < 0.0001)., Conclusions: We found tissue-specific intra-patient variability of IC across different DECT scanner types. Normalization mitigated variability by reducing physiological fluctuations in iodine distribution. After normalization, the scanner type still had a significant effect on iodine variability in the pancreas and liver., Clinical Relevance Statement: Differences in iodine quantification between dual-energy CT scanners can partly be mitigated by normalization, yet remain relevant for specific tissues and inter-scanner comparisons, which should be taken into account at clinical routine imaging., Key Points: • Iodine concentration showed the least variability between scanner types in the kidneys (range 10.92-15.76%) and highest variability in the liver (range 22.85-29.08%). • Normalizing tissue-specific iodine concentrations against the overall iodine load yielded the greatest reduction of variability between scanner types for 2/3 inter-scanner comparisons in the liver and for all (3/3) inter-scanner comparisons in the kidneys and pancreas, respectively. • However, even after normalization, the dual-energy CT scanner type was found to be the factor significantly influencing variability of iodine concentration in the liver and pancreas., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Background and Objectives: Alzheimer disease (AD) copathologies of β-amyloid and tau are common in the Lewy body diseases (LBD), dementia with Lewy bodies (DLB) and Parkinson disease (PD), and target distinct hippocampal subfields compared with Lewy pathology, including subiculum and CA1. We investigated the hypothesis that AD copathologies impact the pattern of hippocampal subregion volume loss and cognitive function in LBD., Methods: This was a cross-sectional and longitudinal, single-center, observational cohort study. Participants underwent neuropsychological testing and 3T-MRI with hippocampal segmentation using FreeSurferV7. PiB-PET and flortaucipir-PET imaging of comorbid β-amyloid (A) and tau (T) were acquired. The association of functional cognition, β-amyloid, and tau loads with hippocampal subregion volume was assessed. The contribution of subregion volumes to the relationship of AD-related deposits on functional cognition was examined with mediation analysis. The effects of AD-related deposits on the rate of subregion atrophy were evaluated with mixed-effects models., Results: Of 103 participants (mean age: 70.3 years; 37.3% female), 52 had LBD with impaired cognition (LBD-I), 26 had normal cognition (LBD-N), and 25 were A- healthy controls (HCs). Volumes of hippocampal subregions prone to AD copathologies, including subiculum ( F = 6.9, p = 0.002), presubiculum ( F = 7.3, p = 0.001), and parasubiculum ( F = 5.9, p = 0.004), were reduced in LBD-I compared with LBD-N and HC. Volume was preserved in CA2/3, Lewy pathology susceptible subregions. In LBD-I, reduced CA1, subiculum, and presubiculum volumes were associated with greater functional cognitive impairment (all p < 0.05). Compared with HC, subiculum volume was reduced in A+T+ but not A-T- participants ( F = 2.62, p = 0.043). Reduced subiculum volume mediated the effect of amyloid on functional cognition (0.12, 95% CI: 0.005 to 0.26, p = 0.040). In 26 longitudinally-evaluated participants, baseline tau deposition was associated with faster CA1 ( p = 0.021) and subiculum ( p = 0.002) atrophy., Discussion: In LBD, volume loss in hippocampal output subregions-particularly the subiculum-is associated with functional cognition and AD-related deposits. Tau deposition appears to accelerate subiculum and CA1 atrophy, whereas Aβ does not. Subiculum volume may have value as a biomarker of AD copathology-mediated neurodegeneration and disease progression.

Background: Changes in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer's disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults., Methods: Seventy-six cognitively unimpaired participants (72 ± 6 years old, 61% female) completed multiple Harvard Automated Phone Task (APT) assessments over 2.0 ± 0.9 years. The Harvard APT consists of three tasks, performed through an automated phone system, in which participants refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and transfer money to pay a bill (APT-Bank). Participants underwent Pittsburgh compound-B and flortaucipir positron emission tomography scans at baseline. We computed distribution volume ratios for a cortical amyloid aggregate and standardized uptake volume ratios for medial temporal and neocortical tau regions. In separate linear mixed models, baseline amyloid by time and tau by time interactions were used to predict longitudinal changes in performance on the Harvard APT tasks. Three-way amyloid by tau by time interactions were also investigated. Lastly, we examined associations between tau and change in Harvard APT scores in exploratory voxel-wise whole-brain analyses. All models were adjusted for age, sex, and education., Results: Amyloid [unstandardized partial regression coefficient estimate (β) = -0.007, 95% confidence interval (95% CI) = (-0.013, -0.001)], and medial temporal tau [β = -0.013, 95% CI = (-0.022, -0.004)] were associated with change over time in years on APT-PCP only, i.e., higher baseline amyloid and higher baseline tau were associated with steeper rate of decline of APT-PCP. Voxel-wise analyses showed widespread associations between tau and change in APT-PCP scores over time., Conclusion: Even among cognitively unimpaired older adults, changes over time in the performance of cognitively complex everyday activities relate to cortical amyloid and widespread cerebral tau burden at baseline. These findings support the link between Alzheimer's disease pathology and function and highlight the importance of measuring everyday functioning in preclinical disease stages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Dubbelman, Diez, Gonzalez, Amariglio, Becker, Chhatwal, Gatchel, Johnson, Locascio, Udeogu, Wang, Papp, Properzi, Rentz, Schultz, Sperling, Vannini and Marshall.)

Background: This study evaluates the association between ICUC trauma and short-form Disabilities of the Arm, Shoulder, and Hand Questionnaire (Quick DASH) scores among patients who underwent surgery for distal radius fractures., Methods: This research gathered patient-reported outcomes (PROs) from patients registered in the ICUC database at a single trauma center. The study involved 76 adult patients who underwent surgical treatment for distal radius fractures before 2023. These patients received a volar locking plate for their distal radius fracture. The research utilized two different PROs to evaluate the patients' conditions. The ICUC trauma score measures functional impairment and pain through two 5-point scale questions, allowing patients to self-assess these aspects. The Quick DASH, comprising 11 questions, was used to evaluate symptoms and functionality of the upper extremity., Results: For patients aged 55.9 ± 15.3 years and 4.6 ± 3.9 years post-op follow-up, the ICUC trauma score was 0.70 ± 0.95, and Quick DASH was 6.07 ± 10.35. A strong correlation between ICUC and Quick DASH was identified (r = 0.71, P < 0.01). The interaction between the ICUC trauma score and age at the surgery to Quick DASH revealed a significant unstandardized partial regression coefficient of 0.19 (95% confidence interval 0.08-0.31; P < 0.01)., Conclusion: This study demonstrated a strong correlation between the ICUC trauma score and the Quick DASH among patients, especially the elderly. It was noted that an elevation in the ICUC trauma score is linked to a more marked increase in the Quick DASH score, particularly in older patients. Given its simplicity and efficacy, the ICUC trauma score may be a viable alternative to the Quick DASH for assessing the patient's clinical outcomes., (© 2024. The Author(s).)

Introduction: It is important to study apathy in Alzheimer's disease (AD) to better understand its underlying neurobiology and develop effective interventions. In the current study, we sought to examine the relationships between longitudinal apathy and regional tau burden in cognitively impaired older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database., Methods: Three hundred and nineteen ADNI participants with mild cognitive impairment (MCI) or AD dementia underwent flortaucipir (FTP) tau positron emission tomography (PET) imaging and clinical assessment with the Neuropsychiatric Inventory (NPI) annually. Longitudinal NPI Apathy (NPI-A) scores were examined in relation to baseline tau PET signal in three a priori selected regions implicated in AD and AD-related apathy (supramarginal gyrus, entorhinal cortex [EC] and rostral anterior cingulate cortex [rACC]). Secondary models were adjusted for global cognition (Mini-Mental State Examination score) and cortical amyloid (florbetapir PET)., Results: Higher baseline supramarginal gyrus and EC tau burden were each significantly associated with greater NPI-A over time, while rACC tau was associated with higher NPI-A but did not predict its trajectory over time. These results were retained for supramarginal and EC tau after adjusting models for global cognition and cortical amyloid., Discussion: Our findings suggest that baseline in vivo tau burden in parietal and temporal brain regions affected in AD, and less so in a medial frontal region involved in motivational control, is associated with increasing apathy over time in older adults with MCI and AD dementia. Future work studying emergent apathy in relation to not only core AD pathology but also circuit level dysfunction may provide additional insight into the neurobiology of apathy in AD and opportunities for intervention., Highlights: Tau (Flortaucipir PET) in regions implicated in AD was associated with increasing apathy over timeCortical amyloid was also found to be a robust predictor of the trajectory of apathyEvidence of synergy between regional tau and amyloid in overall higher levels of apathy., Competing Interests: P.Y.P., C.G., K.J.M., O.U., M.P., and J.L. have nothing to disclose. J.R.G. has received past research support from Merck. G.A.M. has received research salary support from Eisai Inc., Eli Lilly and Company, and Genentech. P.B.R. has received research support from Lilly and Eisai, consulting fees from Acadia, Biogen, ExpertConnect, G.L.G., H.M.P. Global, Leerink, Lundbeck, Medalink, MEDACorp, Medscape, Neurology Week, Novo Nordisk, Noble Insights, and Two Labs, and serves on a DSMB for Synaptogenix. Author disclosures are available in the supporting information., (© 2024 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Depression during pregnancy is increasingly recognized as a worldwide public health problem. If untreated, there can be detrimental outcomes for the mother and child. Anxiety is also often comorbid with depression. Although effective treatments exist, most women do not receive treatment. Technology is a mechanism to increase access to and engagement in mental health services., Objective: The Guardians is a mobile app, grounded in behavioral activation principles, which seeks to leverage mobile game mechanics and in-game rewards to encourage user engagement. This study seeks to assess app satisfaction and engagement and to explore changes in clinical symptoms of depression and anxiety among a sample of pregnant women with elevated depressive symptoms., Methods: This multimethod pilot test consisted of a single-arm, proof-of-concept trial to examine the feasibility and acceptability of The Guardians among a pregnant sample with depression (N=18). Participation included two web-based study visits: (1) a baseline assessment to collect demographic and obstetric information and to assess clinical symptoms and (2) an exit interview to administer follow-up measures and explore user experience. Participants completed biweekly questionnaires (ie, Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7) during the trial to assess depression and anxiety symptom severity. App satisfaction was measured using 2 self-report scales (ie, Mobile Application Rating Scale and Player Experience of Needs Satisfaction scale). Engagement with The Guardians was captured using game interaction metric data. We used backward-eliminated mixed effects longitudinal models to examine the effects of app engagement and satisfaction and length of time in the study on symptoms of depression and anxiety. Content analysis was conducted on qualitative data from exit interviews., Results: The 15-day and 30-day overall app retention rates were 26.6% and 15.1%, respectively. Mixed effects models found significant negative main effects of week in study (β=-.35; t 61 =-3.05; P=.003), number of activities completed (β=-.12; t 61 =-2.05; P=.04), days played (β=-.12; t 58 =-2.9; P=.005), and satisfaction, according to the Mobile Application Rating Scale (β=-3.05; t 45 =-2.19; P=.03) on depressive symptoms. We have reported about similar analyses for anxiety. There is preliminary evidence suggesting harder activities are associated with greater mood improvement than easier activities. Qualitative content analysis resulted in feedback falling under the following themes: activities, app design, engagement, fit of the app with lifestyle, perceived impact of the app on mood, and suggestions for app modifications., Conclusions: Preliminary results from this multimethod study of The Guardians indicate feasibility and acceptability among pregnant women with depression. Retention and engagement levels were more than double those of previous public mental health apps, and use of the app was associated with significant decrease in depressive symptom scores over the 10-week trial. The Guardians shows promise as an effective and scalable digital intervention to support women experiencing depression., (©Rachel C Vanderkruik, Craig Ferguson, Lauren A Kobylski, Joseph J Locascio, Gabriella E Hamlett, Parker C Killenberg, Robert Lewis, Noah Jones, Ella T Rossa, Hannah Dineen, Rosalind Picard, Lee S Cohen. Originally published in JMIR Formative Research (https://formative.jmir.org), 26.01.2024.)

Background: Calciphylaxis is a thrombotic vasculopathy characterized by painful necrotic ulcerations. There are no Food and Drug Administration approved therapies despite high mortality., Objective: To compare mortality and wound healing outcomes in patients treated with hyperbaric oxygen therapy (HBOT) in addition to intravenous sodium thiosulfate (IV STS) versus patients who received IV STS only. Findings were stratified by dialysis status and modality., Methods: 93 patients were included, with 57 patients in the control group (IV STS) and 36 patients in the treatment group (HBOT + IV STS). Mortality data were analyzed with traditional survival analyses and Cox proportional hazard models. Longitudinal wound outcomes were analyzed with mixed effects modeling., Results: Univariate survival analyses showed that full HBOT treatment was associated with significantly (P = .016) longer survival time. Increasing number of HBOT sessions was associated with improved mortality outcomes, with 1, 5, 10 and 20 sessions yielding decreasing hazard ratios. There was also a significant (P = .042) positive association between increasing number of HBOT sessions and increased wound score., Limitations: Data collection was retrospective., Conclusion: HBOT may have a role in the treatment of calciphylaxis with benefits demonstrated in both mortality and wound healing. Larger prospective studies are needed to identify which patients would most benefit from this intervention., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Late-onset GM2 gangliosidosis (LOGG) subtypes late-onset Tay-Sachs (LOTS) and Sandhoff disease (LOSD) are ultra-rare neurodegenerative lysosomal storage disorders presenting with weakness, ataxia, and neuropsychiatric symptoms. Previous studies considered LOTS and LOSD clinically indistinguishable; recent studies have challenged this. We performed a scoping review to ascertain whether imaging and clinical features may differentiate these diseases., Methods: We examined MEDLINE/non-MEDLINE databases up to May 2022. Articles reporting brain imaging findings in genetically/enzymatically confirmed LOGG, symptom onset at age ≥ 10 years (or evaluated at least once ≥18 years) were included, yielding 170 LOGG patients (LOTS = 127, LOSD = 43) across 68 papers. We compared LOTS versus LOSD and performed regression analyses. Results were corrected for multiple comparisons., Results: Age of onset was lower in LOTS versus LOSD (17.9 ± 8.2 vs. 23.9 ± 14.4 years, p = 0.017), although disease duration was similar (p = 0.34). LOTS more commonly had psychosis/bipolar symptoms (35.0% vs. 9.30%, p = 0.011) but less frequent swallowing problems (4.10% vs. 18.60%, p = 0.041). Cerebellar atrophy was more common in LOTS (89.0%) versus LOSD (60.5%), p < 0.0001, with more severe atrophy in LOTS (p = 0.0005). Brainstem atrophy was documented only in LOTS (14.2%). Independent predictors of LOTS versus LOSD (odds ratio [95% confidence interval]) included the presence of psychosis/bipolar symptoms (4.95 [1.59-19.52], p = 0.011), no swallowing symptoms (0.16 [0.036-0.64], p = 0.011), and cerebellar atrophy (5.81 [2.10-17.08], p = 0.0009). Lower age of onset (0.96 [0.93-1.00], p = 0.075) and tremor (2.50 [0.94-7.43], p = 0.078) were marginally statistically significant but felt relevant to include in the model., Interpretation: These data suggest significant differences in symptomatology, disease course, and imaging findings between LOTS and LOSD., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: Increased intestinal permeability seems to be a key factor in the pathogenesis of autoimmune diseases, including celiac disease (CeD). However, it is unknown whether increased permeability precedes CeD onset. This study's objective was to determine whether intestinal permeability is altered before celiac disease autoimmunity (CDA) in at-risk children. We also examined whether environmental factors impacted zonulin, a widely used marker of gut permeability., Methods: We evaluated 102 children in the CDGEMM study from 2014-2022. We included 51 CDA cases and matched controls, who were enrolled for 12 months or more and consumed gluten. We measured serum zonulin from age 12 months to time of CDA onset, and the corresponding time point in controls, and examined clinical factors of interest. We ran a mixed-effects longitudinal model with dependent variable zonulin., Results: Children who developed CDA had a significant increase in zonulin in the 18.3 months (range 6-78) preceding CDA compared to those without CDA (slope differential = β = 0.1277, 95% CI: 0.001, 0.255). Among metadata considered, zonulin trajectory was only influenced by increasing number of antibiotic courses, which increased the slope of trajectory of zonulin over time in CDA subjects (P = .04)., Conclusions: Zonulin levels significantly rise in the months that precede CDA diagnosis. Exposure to a greater number of antibiotic courses was associated with an increase in zonulin levels in CDA subjects. This suggests zonulin may be used as a biomarker for preclinical CeD screening in at-risk children, and multiple antibiotic courses may increase their risk of CDA by increasing zonulin levels., (Copyright © 2024 by the American Academy of Pediatrics.)

Objective: Individuals with epilepsy often have memory difficulties, and older adults with epilepsy are especially vulnerable, due to the additive effect of aging. The goal of this study was to assess factors that are associated with 24-h memory retention in older adults with epilepsy., Methods: Fifty-five adults with epilepsy, all aged >50 years, performed a declarative memory task involving the recall of the positions of 15 card pairs on a computer screen prior to a 24-h ambulatory electroencephalogram (EEG). We assessed the percentage of encoded card pairs that were correctly recalled after 24 h (24-h retention rate). EEGs were evaluated for the presence and frequency of scalp interictal epileptiform activity (IEA) and scored for total sleep. Global slow wave activity (SWA) power during non-rapid eye movement sleep was also calculated., Results: Forty-four participants successfully completed the memory task. Two were subsequently excluded due to seizures on EEG. The final cohort (n = 42) had a mean age of 64.3 ± 7.5 years, was 52% female, and had an average 24-h retention rate of 70.9% ± 30.2%. Predictors of 24-h retention based on multivariate regression analysis when controlling for age, sex, and education included number of antiseizure medications (β = -.20, p = .013), IEA frequency (β = -.08, p = .0094), and SWA power (β = +.002, p = .02)., Significance: In older adults with epilepsy, greater frequency of IEA, reduced SWA power, and higher burden of antiseizure medications correlated with worse 24-h memory retention. These factors represent potential treatment targets to improve memory in older adults with epilepsy., (© 2023 International League Against Epilepsy.)

Isotretinoin is a systemic therapy approved for acne and has historically required lab monitoring in addition to adherence to the iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) given the medication's teratogenic effects. The COVID-19 pandemic resulted in the expansion of telemedicine, acceptance of remote pregnancy tests, and relaxation of lab monitoring practices. A retrospective review of 142 pediatric patients was conducted, and multivariate linear regression was performed to examine differences in prescribing patterns pre-COVID and during COVID. Backward elimination identified gender and the interaction between acne severity and number of systemic treatments tried before isotretinoin as significant factors associated with increased number of visits to isotretinoin initiation, with females requiring more visits before starting isotretinoin at every acne severity level and even after accounting for systemic treatments previously tried. While the changes catalyzed by the pandemic may have improved visit-related burdens for patients and caregivers, female patients with acne continue to be delayed in receiving isotretinoin even when adjusting for acne severity and systemic treatments trialed, underscoring persistent gender disparities in prescribing practices for isotretinoin., (© 2023 Wiley Periodicals LLC.)

Objective: To examine the experience of interracial anxiety among health professionals and how it may affect the quality of their interactions with patients from racially marginalized populations. We explored the influence of prior interracial exposure-specifically through childhood neighborhoods, college student bodies, and friend groups-on interracial anxiety among medical students and residents. We also examined whether levels of interracial anxiety change from medical school through residency., Data Source: Web-based longitudinal survey data from the Medical Student Cognitive Habits and Growth Evaluation Study., Study Design: We used a retrospective longitudinal design with four observations for each trainee. The study population consisted of non-Black US medical trainees surveyed in their 1st and 4th years of medical school and 2nd and 3rd years of residency. Mixed effects longitudinal models were used to assess predictors of interracial anxiety and assess changes in interracial anxiety scores over time., Principal Findings: In total, 3155 non-Black medical trainees were followed for 7 years. Seventy-eight percent grew up in predominantly White neighborhoods. Living in predominantly White neighborhoods and having less racially diverse friends were associated with higher levels of interracial anxiety among medical trainees. Trainees' interracial anxiety scores did not substantially change over time; interracial anxiety was highest in the 1st year of medical school, lowest in the 4th year, and increased slightly during residency., Conclusions: Neighborhood and friend group composition had independent effects on interracial anxiety, indicating that premedical racial socialization may affect medical trainees' preparedness to interact effectively with diverse patient populations. Additionally, the lack of substantial change in interracial anxiety throughout medical training suggests the importance of providing curricular tools and structure (e.g., instituting interracial cooperative learning activities) to foster the development of healthy interracial relationships., (© 2023 The Authors. Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

Background: To date, there is no comprehensive meta-analysis analyzing the association between alopecia areata, anxiety, and depression., Objective: We sought to analyze the existing literature to examine the association between alopecia areata, anxiety, and depression., Methods: We extracted literature from 4 databases including MEDLINE, Embase, PsychINFO, and Web of Science. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (ie, PRISMA) reporting guidelines to finalize a list of relevant articles to be included in our systematic review and meta-analysis. There were no restrictions placed on publication year or age of participants., Results: Eight studies that included 6010 patients with AA and 20 961 control individuals were included in the quantitative analysis. These included 4 cross-sectional studies and 4 case-control studies. Analysis of these studies showed a positive association with anxiety (pooled odds ratio, 2.50; 95% confidence interval, 1.54-4.06) and depression (pooled odds ratio, 2.71; 95% confidence interval, 1.52-4.82)., Limitations: Publication bias may be a limitation of the study., Conclusion: This study suggests that patients with AA are at higher risk of both anxiety and depression. Health care professionals must be cognizant of this higher risk and consider routine assessment of these conditions and referral to appropriate providers when indicated., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to analyze congestive heart failure (CHF) discharges in Florida (USA) post tropical cyclones from 2007 through 2017., Methods: This was a retrospective longitudinal time series analysis of hospital CHF quarterly discharges across Florida using the Healthcare Cost and Utilization Project (HCUP) database. The autoregressive integrated moving average (ARIMA) model was used with correlated seasonal regressor variables such as cyclone frequency, maximum cyclone wind speed, average temperature, and reports of influenza-like illness (ILI)., Results: A total of 3,372,993 patients were identified, with average age in each quarter ranging 72.2 to 73.9 years and overall mortality ranging 4.3% to 6.4%. The CHF discharges within each year peaked from October through December and nadired from April through June with an increasing overall time trend. Significant correlation was found between CHF discharge and the average temperature (P <.001), with approximately 331.8 less CHF discharges (SE = 91.7) per degree of increase in temperature. However, no significant correlation was found between CHF discharges and frequency of cyclones, the maximum wind speed, and reported ILI., Conclusions: This study suggests that with the current methods and the HCUP dataset, there is no significant increase in overall CHF discharges in Florida as a result of recent previous cyclone occurrences.

Objective: Bias in surrogate decision-making can occur when proxy decision-makers overestimate the degree to which their preferences are shared by others, resulting in a projection of their beliefs onto others. The purpose of this study is to assess projection of care partners' preferences onto surrogate assessments of everyday preferences for persons with cognitive impairment (CI) and to address clinical and demographic factors as predictors of projection., Methods: The sample included 116 dyads of persons with CI (Clinical Dementia Rating Scale score ≥ 0.5) and their care partners. The Preferences for Everyday Living Inventory (PELI) was used to assess importance of preferences among persons with CI. Care partners completed two separate PELI assessments: one from the perspective of the persons with CI (i.e., acting as a surrogate decision-maker) and one from their own perspective. To assess for projection of care partners' preferences onto surrogate assessments of preferences for persons with CI, two-step regression with multivariable-adjusted general linear models was used., Results: Significant projection was noted within the PELI domains of autonomous choice, personal growth, and keeping a routine (p < 0.005). More significant cognitive impairment was associated with increased projection within the PELI domains of autonomous choice and personal growth (p < 0.05)., Conclusion: The results of this study suggest that projection of care partners' own preferences may be a significant source of bias in proxy decision-making regarding everyday preferences for persons with CI, particularly for those with more significant CI., (Copyright © 2022 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Both preclinical studies, and more recent clinical imaging studies, suggest that glia-mediated neuroinflammation may be implicated in chronic pain, and therefore might be a potential treatment target. However, it is currently unknown whether modulating neuroinflammation effectively alleviates pain in humans. This trial tests the hypothesis that minocycline, an FDA-approved tetracycline antibiotic and effective glial cell inhibitor in animals, reduces neuroinflammation and may reduce pain symptoms in humans with chronic low back pain., Methods and Analysis: This study is a randomized, double-blind, placebo-controlled clinical trial. Subjects, aged 18-75, with a confirmed diagnosis of chronic (≥ six months) low back pain (cLBP) and a self-reported pain rating of at least four out of ten (for at least half of the days during an average week) are enrolled via written, informed consent. Eligible subjects are randomized to receive a 14-day course of either active drug (minocycline) or placebo. Before and after treatment, subjects are scanned with integrated Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) using [ 11 C]PBR28, a second-generation radiotracer for the 18 kDa translocator protein (TSPO), which is highly expressed in glial cells and thus a putative marker of neuroinflammation. Pain levels are evaluated via daily surveys, collected seven days prior to the start of medication, and throughout the 14 days of treatment. General linear models will be used to assess pain levels and determine the treatment effect on brain (and spinal cord) TSPO signal., Trial Registration Number: ClinicalTrials.gov (NCT03106740)., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The Stroke Preclinical Assessment Network (SPAN) is a multicenter preclinical trial platform using rodent models of transient focal cerebral ischemia to address translational failure in experimental stroke. In addition to centralized randomization and blinding and large samples, SPAN aimed to introduce heterogeneity to simulate the heterogeneity embodied in clinical trials for robust conclusions. Here, we report the heterogeneity introduced by allowing the 6 SPAN laboratories to vary most of the biological and experimental model variables and the impact of this heterogeneity on middle cerebral artery occlusion (MCAo) performance. We included the modified intention-to-treat population of the control mouse cohort of the first SPAN trial (n=421) and examined the biological and procedural independent variables and their covariance. We then determined their impact on the dependent variables cerebral blood flow drop during MCAo, time to achieve MCAo, and total anesthesia duration using multivariable analyses. We found heterogeneity in biological and procedural independent variables introduced mainly by the site. Consequently, all dependent variables also showed heterogeneity among the sites. Multivariable analyses with the site as a random effect variable revealed filament choice as an independent predictor of cerebral blood flow drop after MCAo. Comorbidity, sex, use of laser Doppler flow to monitor cerebral blood flow, days after trial onset, and maintaining anesthesia throughout the MCAo emerged as independent predictors of time to MCAo. Total anesthesia duration was predicted by most independent variables. We present with high granularity the heterogeneity introduced by the biological and model selections by the testing sites in the first trial of cerebroprotection in rodent transient filament MCAo by SPAN. Rather than trying to homogenize all variables across all sites, we embraced the heterogeneity to better approximate clinical trials. Awareness of the heterogeneity, its sources, and how it impacts the study performance may further improve the study design and statistical modeling for future multicenter preclinical trials.

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer's disease (AD) is critical., Objective: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults., Methods: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid., Results: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone., Conclusion: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.

Background: Cognitive decline in Parkinson's disease (PD) is prevalent, insidious, and burdensome during the progression of the disease., Objectives: We aimed to find transcriptome-wide biomarkers in blood to predict cognitive decline and identify patients at high risk with cognitive impairment in PD., Methods: We carried out joint modeling analysis to characterize transcriptome-wide longitudinal gene expression and its association with the progression of mild cognitive impairment (MCI) in PD patients. The average time-dependent area under the curves (AUCs) were used for evaluating the accuracy of the significant joint models. A cognitive survival score (CogSs) derived from joint model was leveraged to predict the occurrence of MCI. All predicting models were built in a discovery cohort with 272 patients and replicated in an independent cohort with 177 patients., Results: We identified five longitudinal varied expression of transcripts that were significantly associated with MCI progression in patients with PD. The most significant transcript IGLC1 joint model accurately predicted the progression of MCI in PD patients in the discovery and replication cohorts (average time-dependent AUCs >0.82). The CogSs derived from the optimal IGLC1 joint model had a high accuracy at early study stage in both cohorts (AUC ≥0.91)., Conclusions: Our transcriptome-wide joint modeling analysis uncovered five blood-based transcripts related to cognitive decline in PD. The joint models will serve as a useful resource for clinicians and researchers to screen PD patients with high risk of development of cognitive impairment and pave the path for Parkinson's personalized medicine. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Background: Extramural vascular invasion (EMVI) is a known poor prognostic factor in colorectal carcinoma; however, its molecular basis has not been defined. This study aimed to assess the expression of molecular markers in EMVI positive colorectal carcinoma to understand their tumor microenvironment., Methods: Immunohistochemistry was performed on tissue microarrays of surgically resected colorectal cancer specimens for immunological markers, and BRAFV600E mutation (and on the tissue blocks for mismatch repair proteins). Automated quantification was used for CD8, LAG3, FOXP3, PU1, and CD163, and manual quantification was used for PDL1, HLA I markers (beta-2 microglobulin, HC10), and HLA II. The Wilcoxon rank-sum test was used to compare EMVI positive and negative tumors. A logistic regression model was fitted to assess the predictive effect of biomarkers on EMVI., Results: There were 340 EMVI positive and 678 EMVI negative chemo naïve tumors. PDL1 was barely expressed on tumor cells (median 0) in the entire cohort. We found a significantly lower expression of CD8, LAG3, FOXP3, PU1 cells, PDL1 positive macrophages, and beta-2 microglobulin on tumor cells in the EMVI positive subset (p ≤ 0.001). There was no association of BRAFV600E or deficient mismatch repair proteins (dMMR) with EMVI. PU1 (OR 0.8, 0.7-0.9) and low PDL1 (OR 1.6, 1.1-2.3) independently predicted EMVI on multivariate logistic regression among all biomarkers examined., Conclusion: There is a generalized blunting of immune response in EMVI positive colorectal carcinoma, which may contribute to a worse prognosis. Tumor-associated macrophages seem to play the most significant role in determining EMVI., (© 2022. Society of Surgical Oncology.)

Purpose: To review the clinical features, microbiology, management, and incidence of bacterial dacryoadenitis at our institution., Methods: This was a case series examining patients with bacterial dacryoadenitis from 2004 to 2020. Charts were reviewed for demographics, comorbidities, presenting symptoms and signs, radiology, microbiology, and management. Main outcomes included need for surgical intervention or inpatient admission., Results: Forty-five patients with bacterial dacryoadenitis had a mean age of 46.1 years. Presenting symptoms included eyelid edema (100%), extraocular motility restriction (53.3%), and purulent discharge (75.5%). Based on computed tomography or magnetic resonance imaging, 9 (20.5%) patients presented with definite abscess and 15 (34%) presented with a phlegmon or early abscess. Eleven patients (24.4%) required surgical drainage. Twenty patients (44.4%) required admission, for an average stay of 4 days (range 2-8 days). Common organisms included Haemophilus influenzae, Streptococcus pneumoniae , and Staphylococcus aureus . Presence of an early abscess or phlegmon correlated with need for drainage (p < 0.01). Extraocular motility restriction correlated with need for drainage (p = 0.02) and admission (p = 0.05). The incidence of bacterial dacryoadenitis at our institution increased as a percentage of confirmed dacryoadenitis cases; from 2004 to 2010 the incidence was 0 to 9.1% per year, while from 2010 to 2019 the incidence ranged from 7.7 to 36.2%. In 2019, our institution had 17 cases (incidence 36.2%) of bacterial dacryoadenitis., Conclusions: Bacterial dacryoadenitis is a major cause of dacryoadenitis, and its incidence may be increasing. It can resolve with minimal complications if managed appropriately, although some patients may require surgical drainage or admission for intravenous antibiotics.

Objective: This manuscript describes the rationale and design of a randomized, controlled trial comparing outcomes with Warfarin vs Novel Oral Anticoagulant (NOAC) therapy in patients with new onset atrial fibrillation after cardiac surgery., Background: New onset atrial fibrillation commonly occurs after cardiac surgery and is associated with increased rates of stroke and mortality. in nonsurgical patients with atrial fibrillation, NOACs have been shown to confer equivalent benefits for stroke prevention with less bleeding risk and less tedious monitoring requirements compared with Warfarin. However, NOAC use has yet to be adopted widely in cardiac surgery patients., Methods: The NEW-AF study has been designed as a pragmatic, prospective, randomized controlled trial that will compare financial, convenience and safety outcomes for patients with new onset atrial fibrillation after cardiac surgery that are treated with NOACs versus Warfarin., Results: Study results may contribute to optimizing the options for stroke prophylaxis in cardiac surgery patients and catalyze more widespread application of NOAC therapy in this patient population., Conclusions: The study is ongoing and actively enrolling at the time of the publication. The trial is registered with clinicaltrials.gov under registration number NCT03702582., Competing Interests: The authors declare no conflict of interests., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To assess the utility of ASL in evaluating patients presenting to the ED with stroke-like symptoms., Methods: ASL and DWI images from 526 consecutive patients presenting to the ED with acute stroke symptoms were retrospectively reviewed. DWI images were evaluated for volume of restricted diffusion using ABC/2. ASL maps were evaluated for decreased, normal, or increased signal. The volume of decreased ASL signal was calculated using the same ABC/2 technique. The volume of decreased ASL signal was correlated with the volume of DWI signal abnormality to identify cases of mismatch (DWI:ASL ratio > 1.8) and to correlate this mismatch with infarct growth on imaging follow-up. NIHSS, length of hospital stay, mRS, and future admission for acute stroke-like symptoms were recorded. Correlations between ASL abnormalities and clinical parameters were evaluated using a two-tailed t-test., Results: Of the 526 patients presenting with acute stroke symptoms, 136 patients had an abnormal ASL scan and 388 patients had a normal ASL scan. Of the 136 patients with abnormal ASL, 84 patients had low ASL signal with 79 of these being related to acute infarcts. Elevated ASL signal was seen in 52 patients, of which 30 of these patients had reperfusion hyperemia related to acute infarctions. ASL had a negative predictive value of 94% for evaluating patients with acute ischemic stroke. A subset of patients with abnormal ASL scans with a discharge diagnosis of acute infarction were found to have an ASL:DWI mismatch (ratio > 1.8) and demonstrated significant lesion growth on follow-up imaging (57%). This included some patients who exhibited low ASL signal before development of diffusion restriction (infarction)., Conclusion: In patients presenting to the ED with acute stroke symptoms, ASL provides information not available with DWI alone. The NPV of ASL for evaluating patients with acute ischemia was 94%., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Neuropsychiatric symptoms (NPS) of dementia are common and may be driven by inability of persons with cognitive impairment (CI) to communicate needs. We addressed the relevance of this unmet-needs model to burden of NPS among persons with milder CI., Methods: The sample included 48 dyads of persons with CI and their care partners. NPS were measured at baseline and follow-up (mean 486 days +/-107 SD). Mixed random and fixed effects longitudinal models were used to evaluate impact of discrepancies between persons with CI and their care partners in everyday preferences (baseline) on changes in NPS over time., Results: Higher levels of underestimation of "social engagement" preferences of persons with CI by care partners were associated with a higher average burden of NPS across all follow-up., Conclusions: This study suggests that unmet-needs may be a useful construct for understanding etiology for NPS across the spectrum of severity of cognitive impairment., (Copyright © 2021 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the patient-reported outcomes among patients with nasal obstruction undergoing two rhinoplasty techniques to a control group. Methods: Prospective longitudinal study in a university-based tertiary care medical center. All patients undergoing functional septorhinoplasty for correction of lateral wall insufficiency between October 2015 and March 2019 were included; n  = 704, mean age (standard deviation) 39.0 (15.4) years, 52.7% females. Patients completed the Nasal Obstruction Symptom Evaluation (NOSE) and FACE-Q subscales pre- and postoperatively. Patients were divided into three cohorts: spreader and lateral crural strut (LCS) grafts ( n  = 141), spreader and alar rim (AR) grafts ( n  = 104), and the control spreader grafts alone ( n  = 218). Results: The median NOSE scores at last postoperative visit were improved from baseline ( p  < 0.001) for all cohorts. The FACE-Q nasal satisfaction median scores also improved postoperatively in all cohorts, AR, LCS, and spreader, respectively ( p  = 0.001, p  < 0.001, and p  < 0.0001). Conclusions: There was no detectable difference in the improved subjective nasal function, nor adverse aesthetic outcomes in the patients with lateral wall insufficiency treated with functional rhinoplasty techniques in this study.

Background: Oral glucose tolerance test (OGTT)-based measures of insulin secretory response have not been validated in pregnancy., Methods: In a secondary analysis of a longitudinal study, participants were studied prepregnancy (n = 40), in early pregnancy (n = 36; 12-14 weeks' gestation), and in late pregnancy (n = 36; 34-36 weeks' gestation). Participants underwent an OGTT, an intravenous glucose tolerance test (IVGTT), and a hyperinsulinemic-euglycemic clamp at each timepoint. We calculated homeostatic model assessment of beta-cell function (HOMA-2B), insulinogenic index (IGI), corrected insulin response (CIR), ratio of the area under the insulin curve and the area under the glucose curve (AUCins/AUCglu), and Stumvoll first-phase estimate (Stumvoll) from OGTT insulin and glucose levels. We used Pearson correlation to compare measures from OGTT and IVGTT. We used mixed effects models to examine longitudinal changes in insulin secretory response., Results: Stumvoll was the only OGTT-based measure that was significantly correlated with first-phase insulin response prior to and across gestation (prepregnancy: r = 0.44, P = 0.01; early pregnancy: r = 0.67, P = 0.0001; late pregnancy: r = 0.67, P = 0.0001). In early and late pregnancy, AUCins/AUCglu had the strongest correlation with first-phase insulin response (early pregnancy: r = 0.79, P < 0.0001; late pregnancy: r = 0.69, P < 0.0001) but was not significantly correlated prepregnancy. IGI and CIR were significantly correlated with first-phase insulin response prepregnancy (IGI: r = 0.50, P = 0.005; CIR r = 0.47, P = 0.008) and in late pregnancy (IGI: r = 0.68, P = 0.0001; CIR r = 0.57, P = 0.002) but not in early pregnancy. HOMA-2B was the weakest correlate of first-phase insulin response. Stumvoll and AUCins/AUCglu recapitulated the longitudinal changes in insulin secretory response observed by IVGTT., Conclusions: Stumvoll and AUCins/AUCglu are valid OGTT-based insulin secretory response measures for pregnancy studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Survivors of aneurysmal subarachnoid hemorrhage (SAH) face a protracted intensive care unit (ICU) course and are at risk for developing refractory hydrocephalus with the need for a permanent ventriculoperitoneal shunt (VPS). Management of the external ventricular drain (EVD) used to provide temporary cerebrospinal fluid diversion may influence the need for a VPS, ICU length of stay (LOS), and drain complications, but the optimal EVD management approach is unknown. Therefore, we sought to determine the effect of EVD discontinuation strategy on VPS rate., Methods: This was a prospective multicenter observational study at six neurocritical care units in the United States. The target population included adults with suspected aneurysmal SAH who required an EVD. Patients were preassigned to rapid or gradual EVD weans based on their treating center. The primary outcome was the rate of VPS placement. Secondary outcomes were EVD duration, ICU LOS, hospital LOS, and drain complications., Results: A rapid EVD wean protocol was associated with a lower rate of VPS placement, including a delayed posthospitalization shunt, in an adjusted Cox proportional analysis (hazard ratio 0.52 [p = 0.041]) and adjusted logistic regression model (odds ratio 0.43 [95% confidence interval 0.18-1.03], p = 0.057). A rapid wean was also associated with 2.1 fewer EVD days (p = 0.007) and saved an estimated 2.5 ICU days (p = 0.049), as compared with a gradual wean protocol. There were fewer nonfunctioning EVDs in the rapid group (odds ratio 0.32 [95% confidence interval 0.11-0.92]). Furthermore, we found that the time to first wean and the number of weaning attempts were important independent covariates that affected the likelihood of receiving a VPS and the duration of ICU admission., Conclusions: A rapid EVD wean was associated with decreased rates of VPS placement, decreased ICU LOS, and decreased drain complications in survivors of aneurysmal SAH. These findings suggest that a randomized multicentered controlled study comparing rapid vs. gradual EVD weaning protocols is justified., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Objectives: Among older people with cognitive impairment and mild dementia, relatively little is known about the factors that predict preferences for everyday living activities and experiences and that influence the relative importance of those activities and experiences., Design: Cross-sectional study., Setting: Participants were recruited from the Massachusetts Alzheimer's Disease Research Center (MADRC) Clinical Core longitudinal cohort., Participants: The sample included 62 community-dwelling older adults with cognitive impairment (Clinical Dementia Rating global score ≥ 0.5)., Measurements: We used the Preferences for Everyday Living Inventory (PELI) to assess preferences for activities and lifestyle experiences among persons with cognitive impairment. Within-subjects analysis of variance was used to test for significant differences in the mean ratings of importance for four domains of the PELI ("autonomous choice," "social engagement," "personal growth," and "keeping a routine"). Multiple regression models were used to relate predictors, including neuropsychiatric symptoms, to importance ratings for each domain., Results: Significant differences were noted in the mean importance ratings of the preferences domains: "social engagement" preferences were rated as most important, followed by "autonomous choice," "personal growth," and "keeping a routine." For the "social engagement" preferences domain, female sex was significantly associated with higher importance of "social engagement," while depressive symptoms (Geriatric Depression Scale-15 scores) were significantly associated with lower importance., Conclusions: This study adds novel insight into the everyday preferences of community-dwelling older adults with cognitive impairment and highlights the impact of a number of factors, particularly level of depression, on how important various everyday experiences are perceived.

Background: Previous work implicates high pro-inflammatory biomarkers in mood disturbance and low brain-derived neurotrophic factor (BDNF) levels in major depression. However, in hormonally-sensitive premenstrual dysphoric disorder (PMDD), BDNF levels are higher when mood is worse. Perimenopausal depression has not been studied to date. We evaluated whether BDNF and inflammatory cytokines predict mood symptoms across the menstrual cycle in hormonally-sensitive perimenopausal depression symptoms., Methods: Data from 49 time points derived from mid-to-late follicular phase [M/L-FP] and peri‑menstrual assessments of 14 perimenopausal women ages 38-52 with ovulatory menstrual cycles 24-35 days long across 1-2 cycles for mood symptoms, BDNF levels, cytokines, gonadal steroids. Depression was assessed with Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI); irritability with Kellner Symptom Questionnaire Anger-Hostility subscale (SQ); overall psychological distress with Profile of Mood States (POMS). Mixed models were run on dependent measures of MADRS (primary endpoint) and other mood outcomes (BDI, POMS, SQ) with independent variables of interest (each biomarker, cycle phase), controlling for cycle number and participant., Results: After FDR adjustment, BDNF levels showed consistent significant positive relationships to MADRS (β=0.00053; p = 0.0028), POMS (β=0.00153; p = 0.0394), SQ (β=0.00053; p = 0.0067), and BDI (β=0.00039; p = 0.0231). Cycle phase did not affect this relationship. No other biomarker consistently predicted affective symptom severity., Limitations: Small sample size and large number of comparisons., Conclusion: In women with perimenopausal depression symptoms, BDNF is elevated in association with more severe mood symptomatology, resembling the pattern in hormonally-sensitive PMDD and suggesting a hormonally-sensitive mood disorder biomarker profile distinct from that of major depression., (Copyright © 2021. Published by Elsevier B.V.)

Protein-coding variants in the GBA gene modulate susceptibility and progression in ~10% of patients with Parkinson's disease (PD). GBA encodes the β-glucocerebrosidase enzyme that hydrolyzes glucosylceramide. We hypothesized that GBA mutations will lead to glucosylceramide accumulation in cerebrospinal fluid (CSF). Glucosylceramide, ceramide, sphingomyelin, and lactosylceramide levels were measured by liquid chromatography-tandem mass spectrometry in CSF of 411 participants from the Parkinson's Progression Markers Initiative (PPMI) cohort, including early stage, de novo PD patients with abnormal dopamine transporter neuroimaging and healthy controls. Forty-four PD patients carried protein-coding GBA variants (GBA-PD) and 227 carried wild-type alleles (idiopathic PD). The glucosylceramide fraction was increased (P = 0.0001), and the sphingomyelin fraction (a downstream metabolite) was reduced (P = 0.0001) in CSF of GBA-PD patients compared to healthy controls. The ceramide fraction was unchanged, and lactosylceramide was below detection limits. We then used the ratio of glucosylceramide to sphingomyelin (the GlcCer/SM ratio) to explore whether these two sphingolipid fractions altered in GBA-PD were useful for stratifying idiopathic PD patients. Idiopathic PD patients in the top quartile of GlcCer/SM ratios at baseline showed a more rapid decline in Montreal Cognitive Assessment scores during longitudinal follow-up compared to those in the lowest quartile with a P-value of 0.036. The GlcCer/SM ratio was negatively associated with α-synuclein levels in CSF of PD patients. This study highlights glucosylceramide as a pathway biomarker for GBA-PD patients and the GlcCer/SM ratio as a potential stratification tool for clinical trials of idiopathic PD patients. Our sphingolipids data together with the clinical, imaging, omics, and genetic characterization of PPMI will contribute a useful resource for multi-modal biomarkers development., (© 2021. The Author(s).)

Background: The goal of this study was to determine the relationship between postoperative weight change and breast cancer-related lymphedema (BCRL)., Methods: In this cohort study, 1161 women underwent unilateral breast surgery for breast cancer from 2005 to 2020 and were prospectively screened for BCRL. Arm volume measurements were obtained via an optoelectronic perometer preoperatively, postoperatively, and in the follow-up setting every 6 to 12 months. Mean follow-up from preoperative baseline was 49.1 months. The main outcome was BCRL, defined as a relative volume change of the ipsilateral arm of ≥10% at least 3 months after surgery., Results: A total of 92 patients (7.9%) developed BCRL. Net weight loss versus net weight gain from baseline to last follow-up was not protective against developing BCRL (hazard ratio, 1.38; 95% confidence interval, 0.89-2.13; P = .152)., Conclusions: Although weight loss may be recommended as part of an individualized lifestyle management program for overall health, weight loss alone may not decrease the risk of developing BCRL., (© 2021 American Cancer Society.)

Background: Following non-traumatic subarachnoid hemorrhage (SAH), in-hospital delayed cerebral ischemia is predicted by two chief events on continuous EEG (cEEG): new or worsening epileptiform abnormalities (EAs) and deterioration of cEEG background frequencies. We evaluated the association between longitudinal outcomes and these cEEG biomarkers. We additionally evaluated the association between longitudinal outcomes and other in-hospital complications., Methods: Patients with nontraumatic SAH undergoing ≥ 3 days of cEEG monitoring were enrolled in a prospective study evaluating longitudinal outcomes. Modified Rankin Scale (mRS) was assessed at discharge, and at 3- and 6-month follow-up time points. Adjusting for baseline severity in a cumulative proportional odds model, we modeled the mRS ordinally and measured the association between mRS and two forms of in-hospital cEEG deterioration: (1) cEEG evidence of new or worsening epileptiform abnormalities and (2) cEEG evidence of new background deterioration. We compared the magnitude of these associations at each time point with the association between mRS and other in-hospital complications: (1) delayed cerebral ischemia (DCI), (2) hospital-acquired infections (HAI), and (3) hydrocephalus. In a secondary analysis, we employed a linear mixed effects model to examine the association of mRS over time (dichotomized as 0-3 vs. 4-6) with both biomarkers of cEEG deterioration and with other in-hospital complications., Results: In total, 175 mRS assessments were performed in 59 patients. New or worsening EAs developed in 23 (39%) patients, and new background deterioration developed in 24 (41%). Among cEEG biomarkers, new or worsening EAs were independently associated with mRS at discharge, 3, and 6 months, respectively (adjusted cumulative proportional odds 4.99, 95% CI 1.60-15.6; 3.28, 95% CI 1.14-9.5; and 2.71, 95% CI 0.95-7.76), but cEEG background deterioration lacked an association. Among hospital complications, DCI was associated with discharge, 3-, and 6-month outcomes (adjusted cumulative proportional odds 4.75, 95% CI 1.64-13.8; 3.4; 95% CI 1.24-9.01; and 2.45, 95% CI 0.94-6.6), but HAI and hydrocephalus lacked an association. The mixed effects model demonstrated that these associations were sustained over longitudinal assessments without an interaction with time., Conclusion: Although new or worsening EAs and cEEG background deterioration have both been shown to predict DCI, only new or worsening EAs are associated with a sustained impairment in functional outcome. This novel finding raises the potential for identifying therapeutic targets that may also influence outcomes., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)