Citations

Abstract Background Cognitive impairment often goes undetected by clinicians due to time constraints, limited expertise, and lack of standardized tools. Structured cognitive assessments improve detection accuracy compared to unstructured clinical judgment. In 2013, the Alzheimer’s Association published recommendations to help primary care clinicians incorporate cognitive assessments into the Medicare Annual Wellness Visit. Since then, advances in cognitive assessment tools, availability of disease‐modifying therapies, and shifting expectations around early diagnosis have highlighted the need for updated guidance. In response, the Alzheimer’s Association is developing an evidence‐based clinical practice guideline for cognitive testing in primary care, using the GRADE approach, informed by a systematic review of the best available evidence. Method A multidisciplinary panel formulated a clinical question to inform the development of this guideline. A systematic review was conducted (search range: 1999‐2024) to evaluate the diagnostic accuracy of ten cognitive tests (5‐Cog, AD8, GPCOG, IQCODE, Mini‐Cog, MIS, MoCA, QDRS, RUDAS, and SLUMS) for the early detection of cognitive impairment (including MCI and dementia), in adults aged 55+ in ambulatory settings. The panel also narratively summarized data on emerging digital tools. Result Forty‐one studies meeting eligibility criteria were included in the systematic review. Results were analyzed separately by test (including short‐IQCODE and short‐MoCA) and for primary care and for ambulatory clinic settings (e.g., neurology, memory disorder clinics), as well as for English and Spanish language, resulting in 21 separate analyses. Only three analyses, all related to MoCA, allowed for meta‐analysis. The panel will use the evidence to inform conditional recommendations for or against each specific test. Conclusion By evaluating the diagnostic performance of selected tests, this guideline aims to support healthcare professionals in primary care settings in effective triaging of individuals who may benefit from further cognitive evaluation. To enhance real‐world applicability, considerations such as administration time, ease of scoring, and diagnostic accuracy ‐ along with appropriate cut‐offs by race/ethnicity, education, and language ‐ should be prioritized. This guideline will be regularly updated over time to reflect emerging evidence and the needs of diverse populations.

Abstract Background Exposure to repetitive head impacts (RHI) is associated with developing chronic traumatic encephalopathy (CTE) neuropathology. Cognitive and behavioral symptoms have been associated with CTE neuropathology, but efforts to define the specific clinical syndrome are ongoing. This study characterizes the current use of centrally acting medications (CAMs), chronic pain, and number of orthopedic surgeries in former American football players and evaluates for associations with cognitive and behavioral symptoms. Methods This study analyzed data from the DIAGNOSE CTE Research Project, which includes 120 former professional football players, 60 collegiate football players, and 56 asymptomatic men without history of RHI. Medical history was obtained by self‐report, and participants completed the Montreal Cognitive Assessment (MoCA), Brief Pain Inventory, Barratt Impulsiveness Scale‐11 (BIS‐11), BRIEF‐A Behavioral Regulation Index (BRI), Beck Depression Inventory‐II (BDI‐II), Beck Anxiety Index (BAI), and Brown‐Goodwin Lifetime History of Aggression adulthood score (BGLHA). Logistic regression assessed the association of CAMs, average pain score, and orthopedic surgeries on the cognitive impairment and neurobehavioral dysregulation components of the NINDS traumatic encephalopathy syndrome (TES) research criteria, in former American football players. Linear regression assessed the associations with MoCA and behavioral scales. Models were adjusted for age, education, race, and years of football played. Results Tables 1 and 2 describe the sample and CAM burden. More orthopedic surgeries, CAMs, and higher average pain were observed in former American football players. Number of CAMs was associated with neurobehavioral dysregulation (OR = 2.18), lower MoCA (β = ‐0.47), and higher BIS‐11 (β = 2.23), BDI‐II (β = 2.01), BRI (β = 3.71), BAI (β = 2.04), and BGLHA (β = 0.68) scores. Higher average pain was associated with neurobehavioral dysregulation (OR = 1.57) and higher BIS‐11 (β = 2.20), BDI‐II (β = 1.98), BRI (β = 2.20), BAI (β = 1.84), and BGLHA (β = 0.52) scores. No associations were observed with orthopedic surgeries. Conclusions In former American football players, the number of CAMs and higher average pain were associated with neurobehavioral dysregulation. No associations were observed with diagnosis of cognitive impairment by TES criteria, though the number of CAMs was associated with decreased MoCA.

Abstract Background Amyloid related imaging abnormality edema (ARIA‐E) occurs in about 19% of individuals with autosomal dominant Alzheimer disease (ADAD) treated with an anti‐amyloid‐b monoclonal antibody (Salloway et al., 2021). In a previously reported case, ARIA‐E appeared to colocalize with decreases in PiB‐PET uptake (Joseph‐Mathurin, Llibre‐Guerra, et al, 2022), suggesting an association between amyloid‐b (Aβ) removal and ARIA‐E. Here, we compare longitudinal neuroimaging and corresponding neuropathology in an ADAD individual treated with gantenerumab, who experienced multiple ARIA‐E episodes as sulcal effusions that resolved by the end of the four‐year trial. Methods PiB‐PET and MRI were collected pre‐ and post‐randomization (2 and 4 years). The participant consented to brain donation, which was received a year after trial completion. Four tissue samples were taken from the location of the ARIA‐E in the parieto‐occipital left hemibrain as identified by MRI (one block contained the sulcus affected by ARIA‐E; the rest of the coronal section was captured in the remaining three blocks). Area fractions (AFs) of Aβ (10D5 immunohistochemistry (IHC)), tauopathy (PHF1), microglia (Iba1), and astrocytes (GFAP) in one sulcal region of interest (ROI) from each block and PiB‐PET SUVRs of corresponding ROIs were extracted ( n = 4, Figure 1). Additionally, we included PiB‐PET SUVRs corresponding to ARIA‐E findings observed in the right hemisphere at baseline, two‐year, and four‐year visits ( n = 6). Results Overall PiB‐PET uptake increased during the first two years (before ARIA‐E) and decreased during the last two years (including ARIA‐E episodes) (0.03±0.05 vs. ‐0.04±0.04 SUVR/year, p ‐value=0.01, Figure 2). The decrease seemed more pronounced in ARIA‐E ROIs versus normal‐appearing sulcus ROIs (‐0.05±0.04 vs. ‐0.02±0.03 SUVR/year). Lower PiB uptake at last visit appeared associated with lower Aβ AF (estimates=0.03±0.01, p ‐value=0.07). The ARIA‐E ROI had an Aβ AF of 0.009 while normal‐appearing sulcus ROIs had a mean of 0.02+0.003 (Figure 3). AFs for tauopathy, microglia, and astrocytes were within the range of those of normal‐appearing sulcus ROIs, suggesting an Aβ‐specific effect, although unexamined markers may play a role. Conclusions Our preliminary findings indicated that ARIA‐E is associated with longitudinal PiB‐PET decrease and Aβ AF, supporting the link between ARIA‐E, changes in PiB‐PET, and local Aβ removal observed at autopsy. Funding : K01AG080123; U01AG042791; R01AG046179; R01AG053267

Abstract Background The Joint Propagation Model (JPM)‐based CenTauR scale was recently introduced to harmonize tau‐PET quantification across different radiotracers. This study examined how CenTauR harmonization enhances the comparability of tau‐PET quantification across matched cohorts using different tracers. The evaluation focused on three key aspects: (1) comparing tau‐PET positivity rates as defined by CenTauR, (2) evaluating its diagnostic accuracy for symptomatic AD, and (3) analyzing longitudinal changes in tau‐PET rates over time. Method The JPM, developed by the CPAD‐led Tau PET Harmonization Working Group (Leuzy et al., Alzheimers Dement. 2024; Figure 1A), models relationships between anchor point subjects and head‐to‐head tau‐PET SUVR data onto the CenTauR scale, providing conversion equations for multiple tracers. JPM equations were applied to [¹⁸F]flortaucipir SUVR (Meta‐temporal ROI) data from 561 cognitively impaired participants in the ADNI and OASIS‐3 studies. Using ROC analysis, we determined the CenTauR cut‐off for positivity (T+) that maximized the Youden index for discriminating between FDA‐approved positive/negative visual reads. Three separate cohorts, scanned using [¹⁸F]flortaucipir (ADNI), [¹⁸F]MK‐6240 (CPAS), and [¹⁸F]RO‐948 (BioFINDER‐2), were matched 1:1 by age, MMSE, amyloid‐β, and clinical diagnosis. CenTauR‐based metrics were compared across these cohorts. Result A cut‐off of 18 CenTauRs was found to optimally classify [ 18 F]flortaucipir PET visual reads (Figure 1B). The matching procedure identified 1089 participants (363 per cohort). The frequency of T+ using the 18 CenTauRs cut‐off for the Meta‐Temporal ROI was highly comparable across tracers across groups, except for the Aβ‐positive cognitively unimpaired group, where variability was more pronounced due to a smaller sample size (Figure 2A). Similarly, tau‐PET discriminative accuracy for symptomatic AD vs controls remained similar across [ 18 F]flortaucipir and [ 18 F]MK‐6240 (Figure 2B). In a separate sample of 212 matched participants from ADNI ([¹⁸F]flortaucipir) and AIBL ([¹⁸F]MK‐6240) with baseline and 1‐year follow‐up tau‐PET scans, 1‐year change in CenTauRs was comparable (Figure 2C). An exploratory voxelwise transformation, utilizing the Meta‐Temporal conversion equation in a representative case scanned with both [¹⁸F]flortaucipir and [¹⁸F]MK‐6240, demonstrates the potential for voxelwise CenTauR harmonization (Figure 3). Conclusion These analyses suggest that CenTauR harmonization increases the comparability of tau‐PET data acquired with different tracers. Additional validation analyses with larger cohorts including other radiotracers ([¹⁸F]PI‐2620) are underway.

Objective: To examine the association of extent of otosclerotic plaque using high-resolution photon-counting computed tomography (PCCT) with hearing and surgical outcomes. Study design: Historical cohort. Setting: Large academic center. Patients: Patients with otosclerosis who completed PCCT imaging at time of initial evaluation. Interventions: Observation, surgery. Main outcome measures: Audiometric data. Results: A total of 53 ears were eligible for study. The mean age at PCCT was 51 years (SD: 14). The mean extent of oval window otosclerotic plaque measured in radial degrees was 112 (SD: 65) and the mean otosclerotic depth was 1.6mm (SD: 0.6). The mean air-bone gap pure-tone average was 18 dB (SD: 12) and the mean Carhart degree was 9 dB (SD: 10). The radial degrees of oval window extent were not significantly associated with air-bone gap (correlation coefficient: 0.14; P =0.3) or Carhart degree (correlation coefficient: 0.04; P =0.8). Likewise, otosclerotic plaque depth was not significantly associated with air-bone gap (correlation coefficient: −0.19; P =0.2) or Carhart degree (correlation coefficient: −0.08; P =0.6). After PCCT, 22 ears underwent surgery. In this subset, oval window extent and plaque depth were not significantly associated with the postoperative changes in air-bone gap or high-frequency thresholds. Conclusions: Despite enhanced visualization of subtle abnormalities with PCCT imaging, the extent of oval window otosclerotic plaque, measured in angular degrees and depth, was not associated with hearing loss at time of initial evaluation or postoperative audiologic changes in patients with otosclerosis.

Objective: To evaluate the impact of cochlear implantation (CI) and simultaneous endolymphatic sac decompression (ELSD) on vestibular and audiometric outcomes in patients with advanced Ménière disease (MD). Study design: Historical cohort. Setting: Tertiary academic medical center. Patients: Patients with medically refractory MD who underwent CI with or without simultaneous ELSD from 2000 through 2024. Interventions: CI with or without ELSD. Main outcome measures: Post-CI patient-reported changes in vertigo severity and frequency, Consonant-Nucleus-Consonant word (CNCw) scores, and AzBio sentences in quiet scores. Results: Ninety-nine patients with preoperative vertigo secondary to MD were eligible for study, including 17 (17%) who underwent simultaneous ELSD. In total, 15 (88%) and 2 (12%) of the 17 patients with simultaneous ELSD reported improvement and stability in vertigo severity, respectively; in comparison, 26 (32%), 40 (49%), and 16 (20%) of the 82 patients with CI alone reported improvement, stability, and worsening in vertigo severity, respectively ( P <0.001). Likewise, 15 (88%) and 2 (12%) of the patients with simultaneous ELSD reported improvement and stability in vertigo frequency, respectively, whereas 21 (26%), 43 (52%), and 18 (22%) of patients with CI alone reported improvement, stability, and worsening in vertigo frequency, respectively ( P <0.001). Post-CI speech recognition scores were not significantly different between the simultaneous ELSD and CI alone groups [median (IQR) CNCw 70 (38 to 82) vs. 72 (58 to 82) and median (IQR) AzBio quiet 87 (67 to 96) vs. 87 (73 to 94), respectively]. Conclusions: In patients with MD, CI with simultaneous ELSD provides improvement in vertigo symptoms and similar audiometric outcomes when compared with CI alone. In appropriately selected patients with both refractory vestibular symptoms and sensorineural hearing loss meeting criteria for implantation, CI with simultaneous ELSD offers improvement in severity and frequency of vertigo as well as successful auditory rehabilitation.

Abstract In phase 3 oncology clinical trials, identifying and understanding potential sources of differential censoring (DC), which describes censoring imbalance between treatment arms, in overall survival (OS) endpoints is vital to reduce bias and misinterpretation of OS benefit. Among 322 trials, 34 (11%) trials exhibited DC overrepresented in the control arm (DCC). Compared to trials without DC or those with DC overrepresented in the experimental arm (DCE), trials with DCC showed higher rates of OS benefit (56% vs. 32%; odds ratio [OR] = 2.26, 95% CI = 1.04 to 4.90; P = .04) and were associated with patient withdrawal (median 8.0% vs. 3.8%; P = .0002), lack of double blinding (15% vs. 48%, OR = 0.19, 95% CI = 0.06 to 0.56; P = .003), and better global quality of life in the experimental arm (32% vs. 13%, OR = 3.01, 95% CI = 1.26 to 7.19; P = .01). OS DCC is a prominent challenge that requires rigorous trial design and comprehensive patient and mortality follow-up to reduce bias in interpreting OS benefit.

Abstract Context Adult growth hormone (GH) deficiency (GHD) is characterized by metabolic abnormalities caused by insufficient GH production. Lonapegsomatropin, a prodrug administered once weekly, was designed to provide sustained release of unmodified somatropin to reduce the burden of daily somatropin injections. Objective This work aimed to evaluate the efficacy and safety of lonapegsomatropin vs placebo as treatment for adults with GHD. Methods The foresiGHt trial was a multicenter, randomized, parallel-arm, placebo-controlled (double-blind) and active-controlled (open-label) trial (NCT04615273) conducted at 116 centers in North America, Europe, and Asia-Pacific. The trial randomly assigned and dosed 259 adults with GHD. Participants were randomly assigned 1:1:1 to receive once-weekly lonapegsomatropin, once-weekly placebo, or daily somatropin for 38 weeks. The primary efficacy end point was change from baseline in trunk percent fat at week 38. Secondary efficacy end points included change from baseline in trunk fat mass and total body lean mass. Results At week 38, lonapegsomatropin significantly reduced trunk percent fat (−1.68% vs +0.37%; least squares [LS] mean difference −2.04%; P &lt; .001), increased total body lean mass (+1.60 kg vs −0.11 kg; LS mean difference 1.70 kg; P &lt; .0001), and reduced trunk fat mass (−0.48 kg vs +0.22 kg; LS mean difference −0.70 kg; P = .0053) vs placebo. The safety and tolerability profile of lonapegsomatropin was comparable to somatropin. Conclusion The foresiGHt trial met its primary efficacy end point by demonstrating superiority of lonapegsomatropin vs placebo with similar safety and tolerability, supporting its potential as a once-weekly treatment option for adults with GHD.

Introduction Despite the identification of multiple susceptibility loci by genome-wide association studies (GWAS), considerable chronic obstructive pulmonary disease (COPD) heritability remains unexplained. Aim To identify interaction networks of airway epithelial cell DNA methylation in COPD and further explore potential correlations with airway bacterial composition, as potentially collective regulators of biological pathways influencing COPD severity. Methods Using DNA isolated from bronchial airway brushings of 67 ever-smokers (>20 pack-years) from the SubPopulations and InteRmediate Outcomes Measures in COPD Study (SPIROMICS), we assessed proportion of DNA methylation (β) by epigenome-wide association study (EWAS) and examined associations of differentially methylated CpG probes (DMPs) with risk for moderate-to-severe COPD (N=34) versus absent or mild COPD (N=33). We tested co-methylation modules generated by Weighted Correlation Network Analyses (WGCNA) for associations with moderate-to-severe COPD and with bacterial genus-level relative abundances (16S rRNA sequencing). Results EWAS-identified nominally significant DMPs enriched for lung function GWAS loci. Eigengenes in six WGCNA modules were associated with moderate-to-severe COPD (false discovery rate <0.05). Four of those modules were enriched for forced expiratory volume in 1 s/forced vital capacity GWAS loci, and five overlapped with DMPs from EWAS. Overlapping CpG loci in three COPD-associated modules were adjacent to mucin genes; one had 10 genes highly ranked by connectivity with MUC5B, including important pathway genes: B3GNT6 , DGKI and ITGA8 . CpGs in an independent COPD-associated module showed the most correlations with Rothia , with directionality suggestive of negative associations with moderate-severe COPD. Conclusions Bronchial epithelial DNA methylation modules enriched for lung function GWAS loci associate with COPD severity in SPIROMICS. Potential module relationships to bronchial bacterial composition require further validation.

Abstract The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.