Citations

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder with significant environmental factors, including diet, that influence its onset and progression. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored the KD’s molecular impact for markers of AD therapeutic potential. The BEAM diet study simultaneously profiled the KD’s effect on the lipidome, blood and cerebrospinal metabolome, and microbiome of both cognitively impaired and cognitively normal individuals. The findings summarized here assess the biological impact of a Modified Mediterranean KD in the context of Alzheimer’s disease treatment and prevention.MethodBEAM involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean‐ketogenic diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6‐week washout period. We employed HPLC‐MS/MS lipidomics profiling in plasma, nuclear magnetic resonance (NMR)‐based metabolomics to profile serum and CSF, and metagenomics profiling on fecal samples before and after each diet to assess dietary‐induced changes.ResultThe MMKD led to significant alterations in the blood, CSF, and microbiome. These changes included a global elevation across all plasmanyl and plasmenyl ether lipid species, improved modifiable risk factors, like increased HDL‐C and reduced BMI, the reversal of serum metabolic disturbances linked to AD such as an increase in valine levels, and a reduction in systemic inflammation. Leveraging prior clinical studies on AD (n = 1,912), we found that MMKD was inversely associated with the peripheral lipidomic signature of prevalent and incident AD. In the CSF, the MMKD was linked to modified amino acid levels and the breakdown of branched‐chain amino acids (BCAAs). Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. In addition, participants with MCI on the MMKD had lower levels of GABA‐producing microbes and GABA, and higher levels of GABA‐regulating microbes.ConclusionOur findings highlight that MMKD can improve AD‐related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood‐CSF barrier.Funding: Alzheimer’s Gut Microbiome Project, NIA U19AG063744

AbstractBackgroundWeakened white matter (WM) integrity is highly associated with dementia risk. Still, not everyone with WM changes develops dementia, suggesting the important role modifiable lifestyle factors may have in reducing dementia risk. We investigated how social relationships in mid‐life may modify the association between WM integrity and incident dementia risk within race and sex subgroups.MethodIn 1,679 Atherosclerosis Risk in Community (ARIC) study participants who were dementia‐free in mid‐life, psychosocial health was assessed via self‐reported questionnaires and participants were classified as having strong or poor social relationships in mid‐life (visit 2: 1990‐1992). Through diffusion tensor imaging, WM integrity was evaluated with 3T brain MRI (visit 5: 2011 – 2013); fractional anisotropy (FA) and mean diffusivity (MD) were estimated. Incident dementia cases were identified from visit 5 through December 31, 2019, with ongoing surveillance. Relative contributions of social relationships and WM integrity to incident dementia were evaluated in Cox‐proportional hazard regression models with race and race‐sex as interaction terms, and in stratified models (White Females, Black Females, White Males, Black Males).ResultSignificant three‐way interactions were observed between race, WM integrity, and mid‐life social relationships (p‐interaction<0.01). In Black participants with strong mid‐life social relationships, higher MD (hazard ratio (HR): 0.93, 95% CI: 0.63 – 1.38) and lower FA (HR: 1.25, 95% CI: 0.84 – 1.86) were not associated with the risk of dementia, although in Black participants with poor social relationships, higher MD remained a significant risk factor for dementia. However, across all White participants, higher MD and lower FA were associated with the risk of dementia, regardless of mid‐life social relationships (Table 1; Figure 1). Analysis of three‐way interactions between race‐sex, WM integrity, and mid‐life social relationships suggested that effect modification by mid‐life social relationships was most evident in Black Females, respective to other groups (Table 2; Figure 1).ConclusionThe contribution of WM integrity to dementia risk may be lower in Black participants with strong social relationships in mid‐life, particularly in Black Females. Further understanding of how contextual social factors may influence brain health in diverse populations should be examined in future studies and intervention efforts.

AbstractBackgroundWeakened white matter (WM) integrity is highly associated with dementia risk. Still, not everyone with WM changes develops dementia, suggesting the important role modifiable lifestyle factors may have in reducing dementia risk. We investigated how social relationships in mid‐life may modify the association between WM integrity and incident dementia risk within race and sex subgroups.MethodIn 1,679 Atherosclerosis Risk in Community (ARIC) study participants who were dementia‐free in mid‐life, psychosocial health was assessed via self‐reported questionnaires and participants were classified as having strong or poor social relationships in mid‐life (visit 2: 1990‐1992). Through diffusion tensor imaging, WM integrity was evaluated with 3T brain MRI (visit 5: 2011 – 2013); fractional anisotropy (FA) and mean diffusivity (MD) were estimated. Incident dementia cases were identified from visit 5 through December 31, 2019, with ongoing surveillance. Relative contributions of social relationships and WM integrity to incident dementia were evaluated in Cox‐proportional hazard regression models with race and race‐sex as interaction terms, and in stratified models (White Females, Black Females, White Males, Black Males).ResultSignificant three‐way interactions were observed between race, WM integrity, and mid‐life social relationships (p‐interaction<0.01). In Black participants with strong mid‐life social relationships, higher MD (hazard ratio (HR): 0.93, 95% CI: 0.63 – 1.38) and lower FA (HR: 1.25, 95% CI: 0.84 – 1.86) were not associated with the risk of dementia, although in Black participants with poor social relationships, higher MD remained a significant risk factor for dementia. However, across all White participants, higher MD and lower FA were associated with the risk of dementia, regardless of mid‐life social relationships (Table 1; Figure 1). Analysis of three‐way interactions between race‐sex, WM integrity, and mid‐life social relationships suggested that effect modification by mid‐life social relationships was most evident in Black Females, respective to other groups (Table 2; Figure 1).ConclusionThe contribution of WM integrity to dementia risk may be lower in Black participants with strong social relationships in mid‐life, particularly in Black Females. Further understanding of how contextual social factors may influence brain health in diverse populations should be examined in future studies and intervention efforts.

AbstractBackgroundThe Progressive Supranuclear Palsy Quality of Life (PSP‐QoL) scale is a 45‐question participant‐completed questionnaire used to evaluate physical and cognitive task difficulties. Participants enrolled in the ALLFTD research program are asked to complete this questionnaire annually during their study visits.MethodPSP‐QoL responses were analyzed at baseline visits. Our analysis focused on responses to the overall satisfaction of life (range 0‐100, with 0 being extremely dissatisfied and 100 being extremely satisfied) relative to disease severity (CDR®+NACC‐FTLD global scores) and as a function of clinical phenotypes. A Kruskal‐Wallis test was used to compare overall satisfaction ratings against CDR®+NACC‐FTLD global score.Result788 PSP‐QoL survey responses were analyzed (participant mean age 55.3 ±15 years, 50.5% female). Analysis included responses from 372 (47.2%) asymptomatic participants (CN; CDR®+NACC‐FTLD = 0), 140 prodromal (17.8%) CDR®+NACC‐FTLD = 0.5, 160 (20.3%) CDR®+NACC‐FTLD = 1, 106 (13.5%) CDR®+NACC‐FTLD 2, and 10 (1.3%) CDR®+NACC‐FTLD = 3. All symptomatic groups were similar in PSP‐QOL overall satisfaction of life rating: (mean overall satisfaction CDR®+NACC‐FTLD = 0.5: 74.5 (SD 22.5); CDR®+NACC‐FTLD = 1: 74.1 (SD 24.7) and CDR®+NACC‐FTLD = 2/3: 74.1 (SD 25.8)), but these differed from asymptomatic (cognitively normal): (mean 83.7, (SD 14.6); p<0.0001). Similarly, when including the CN group and symptomatic phenotype groups, a statistically significant difference in ratings was seen: mean overall satisfaction CN = 83.7 (SD 14.7), MCI = 78.3 (SD 16.6), PPA = 71.6 (SD 26.9), PSP = 66.3 (SD 28.2), bvFTD = 76.8 (SD 23.8), and other = 70.6 (SD 23.2). However, even after removing the CN group, a difference amongst symptomatic phenotypes remained (p = 0.036).ConclusionMean overall life satisfaction as measured by the PSP QoL questionnaire was lower in all symptomatic compared to clinically normal participants, regardless of disease severity or phenotype. Further longitudinal analyses are needed to better understand how clinical progression impacts overall satisfaction of life.

Background A variety of clinically important benchmarks of success (CIBS) have been defined for total shoulder arthroplasty (TSA) to quantify success. However, it is unclear how the preoperative status of the patient influences their likelihood of achieving each CIBS. Questions/purposes (1) What proportion of patients achieve commonly used CIBS after TSA? (2) Is there a relationship between a patients’ preoperative function and their probability of achieving different CIBS? (3) Does there exist preoperative ranges for each outcome measure that are associated with greater achievement of CIBS? Methods We retrospectively queried a multicenter shoulder arthroplasty database for primary anatomic TSA (aTSA) and reverse TSA (rTSA). A total of 2041 aTSAs and 3205 rTSAs were included. The mean ± SD age at time of surgery was 66 ± 9 years for aTSAs and 72 ± 8 years for rTSAs. In all, 51% (1049 of 2041) of aTSAs and 61% (1955 of 3205) of rTSAs were in patients who were women. For aTSAs, osteoarthritis with an intact rotator cuff was the most common preoperative diagnosis (92% [1869 of 2041]). For rTSAs, the most common preoperative diagnoses included rotator cuff tear arthropathy (40% [1280 of 3205]), osteoarthritis with an intact rotator cuff (24% [780 of 3205]), osteoarthritis with a torn rotator cuff (20% [632 of 3205]), and massive rotator cuff tear (10% [309 of 3205]). Outcomes were evaluated at latest follow-up (aTSA 61 ± 36 months, rTSA 47 ± 26 months) and consisted of ROM (abduction, forward elevation, external and internal rotation) as well as the most commonly used outcome scores: the Simple Shoulder Test (SST), Constant score, American Shoulder and Elbow Surgeons (ASES) score, University of California, Los Angeles (UCLA) score, Shoulder Pain and Disability Index (SPADI), and the Shoulder Arthroplasty Smart (SAS) score. The CIBS that we evaluated included the minimum clinically important difference (MCID), substantial clinical benefit (SCB), patient acceptable symptom state (PASS), minimum clinically important percentage of maximal possible improvement (MCI-%MPI), and substantial clinically important percentage of maximal possible improvement (SCI-%MPI). Prosthesis-specific anchor-based CIBS were adopted from prior publications on patients from this database. Multivariable regression was performed to identify the relationship between preoperative outcome measures and achievement of CIBS. Additionally, receiver operating characteristic (ROC) curve analyses were performed to determine whether thresholds in preoperative outcome measures were associated with achieving CIBS. Results For all ROM measures and outcome scores, poorer preoperative ROM was associated with greater odds of achieving the MCID and SCB but lower odds of achieving the PASS. For the SST and the two scores without ceiling effects (the Constant and SAS scores), poorer preoperative outcome scores were associated with greater odds of achieving the MCI-%MPI and SCI-%MPI, but no association was demonstrated for the ASES, SPADI, and UCLA scores. Graphical analysis demonstrated that patients with greater preoperative ROM and outcome scores had a lower probability of achieving the MCID and SCB but a higher probability of achieving the PASS. For outcome scores with known ceiling effects, patients with more favorable preoperative outcome scores were more likely to achieve the MCI-%MPI and SCI-%MPI than the MCID and SCB, respectively. For outcome scores without ceiling effects, patients undergoing aTSA were more likely to achieve the MCID, MCI-%MPI, and the SCI-%MPI than the SCB, but no clear trend was identified for patients undergoing rTSA. On ROC curve analysis, identified thresholds were reasonably accurate (area under the curve > 0.7) for achievement of measures of absolute improvement (the MCID and SCB), but not for absolute postoperative status (the PASS) or relative improvement (the MCI-%MPI and SCI-%MPI). Conclusion While most patients reported being “much better” (aTSA 75%, rTSA 76%) or “better” (aTSA 15%, rTSA 18%) compared with before surgery, 10% of aTSAs and 6% of rTSAs were either “unchanged” or “worse.” Patients’ likelihood of achieving CIBS depends in part on their baseline function and whether success is defined as absolute improvement, absolute postoperative status, or relative improvement. Patients with more favorable preoperative status are more likely to achieve CIBS that evaluate relative improvement (the MCI-%MPI and SCI-%MPI) than absolute improvement (the MCID and SCB). Future studies are needed to determine which individual CIBS or combinations thereof most accurately represent clinically relevant benefit. Level of Evidence Level III, therapeutic study.

Abstract INTRODUCTION The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. METHODS The workgroup identified key research questions that guided a systematic literature review on clinical amyloid/tau PET. Building on this review, the workgroup developed 17 clinical scenarios in which amyloid or tau PET may be considered. A modified Delphi approach was used to rate each scenario by consensus as “rarely appropriate,” “uncertain,” or “appropriate.” Ratings were performed separately for amyloid and tau PET as stand‐alone modalities. RESULTS For amyloid PET, seven scenarios were rated as appropriate, two as uncertain, and eight as rarely appropriate. For tau PET, five scenarios were rated as appropriate, six as uncertain, and six as rarely appropriate. DISCUSSION AUC for amyloid and tau PET provide expert recommendations for clinical use of these technologies in the evolving landscape of diagnostics and therapeutics for Alzheimer's disease. Highlights A multidisciplinary workgroup convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging updated the appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. The goal of these updated AUC is to assist clinicians in identifying clinical scenarios in which amyloid or tau PET may be useful for guiding the diagnosis and management of patients who have, or are at risk for, cognitive decline These updated AUC are intended for dementia specialists who spend a significant proportion of their clinical effort caring for patients with cognitive complaints, as well as serve as a general reference for a broader audience interested in implementation of amyloid and tau PET in clinical practice.

Abstract High-dose methotrexate (MTX) results in high rates of acute kidney injury (AKI), neutropenia, and hepatotoxicity. Glucarpidase is a recombinant enzyme that cleaves MTX, but clinical data supporting its use are scarce. We examined the association between glucarpidase administration and outcomes in adults with MTX-AKI from 28 cancer centers across the United States using a sequential target trial emulation framework. The primary end point was kidney recovery at hospital discharge, defined as survival to discharge with serum creatinine &lt;1.5-fold baseline and without dialysis dependence. Key secondary end points were time to kidney recovery, neutropenia, and transaminitis on day 7, and time to death. Using multivariable logistic and Cox regression models, we compared outcomes in patients who received glucarpidase within 4 days following MTX initiation with those in patients who did not. Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase. Overall, 183 (25.8%) had a primary end point event. Glucarpidase receipt was associated with a 2.70-fold higher adjusted odds of kidney recovery (95% confidence interval [CI], 1.69–4.31) compared with no glucarpidase receipt. Patients treated with glucarpidase also had faster time to kidney recovery (adjusted hazard ratio [aHR], 1.88; 95% CI, 1.18–3.33) and lower risks of grade ≥2 neutropenia (adjusted odds ratio [aOR], 0.50; 95% CI, 0.28–0.91) and grade ≥2 transaminitis (aOR, 0.50; 95% CI, 0.28–0.91) on day 7. There was no difference in time to death (aHR, 0.76; 95% CI, 0.49–1.18). These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI.

BACKGROUND Posttraumatic retroclival hematomas are rare pathologies among pediatric patients and can result in cranial nerve palsies. The authors sought to survey the literature and characterize the risk factors, treatment considerations, and overall outcomes for pediatric patients experiencing posttraumatic retroclival hematomas. OBSERVATIONS A search of the Ovid Embase, Scopus, PubMed, and Web of Science databases from January 1986 to May 2024 was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Additionally, the authors report a novel case of pediatric retroclival hematoma. The systematic review identified 41 eligible articles describing 64 individual cases of posttraumatic clival/retroclival hematoma in pediatric patients. The incidence of abducens nerve palsy in the setting of posttraumatic retroclival hematoma was 40%, and the rate of complete recovery of abducens nerve function was 73%. Analyses revealed that a higher initial Glasgow Coma Scale (GCS) score correlated with general neurological recovery (p < 0.05). However, no significant difference was found in GCS scores between patients with complete and those with incomplete abducens nerve recovery. LESSONS There is a high rate of spontaneous recovery of abducens nerve function in patients with abducens palsy in the setting of posttraumatic retroclival hematoma. While initial GCS scores can predict general neurological recovery, factors influencing abducens nerve palsy resolution remain unclear. https://thejns.org/doi/10.3171/CASE24474

Background: This study aimed to explore the potential associations between voice metrics of patients with PD and their motor symptoms. Methods: Motor and vocal data including the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III), Harmonic–Noise Ratio (HNR), jitter, shimmer, and smoothed cepstral peak prominence (CPPS) were analyzed through exploratory correlations followed by univariate linear regression analyses. We employed these four voice metrics as independent variables and the total and sub-scores of the UPDRS-III as dependent variables. Results: Thirteen subjects were included, 76% males and 24% females, with a mean age of 62.9 ± 10.1 years, and a median Hoehn and Yahr stage of 2.3 ± 0.7. The regression analysis showed that CPPS is associated with posture (UPDRS-III posture scores: β = −0.196; F = 10.0; p = 0.01; R2 = 0.50) and UPDRS-III postural stability scores (β = −0.130; F = 5.57; p = 0.04; R2 = 0.35). Additionally, the associations between CPPS and rapid alternating movement (β = −0.297; p = 0.07), rigidity (β= −0.36; p = 0.11), and body bradykinesia (β = −0.16; p = 0.13) showed a trend towards significance. Conclusion: These findings highlight the potential role of CPPS as a predictor of postural impairments secondary to PD, emphasizing the need for further investigation.