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Background: Tai Chi Chuan (TCC) is considered a mind and body practice of Chinese origin, considered as an intangible cultural heritage of humanity by UNESCO, and recommended by the World Health Organization as a therapeutic approach to prevent falls. Objective: To assess the effects of TCC on older adult's balance. Methods: A systematic review of randomized clinical trials was conducted by two independent reviewers using the ROB2 tool to assess the risk of bias under the following databases: PubMed, SCOPUS, Web of Science, PEDro, Embase, Cochrane, CINAHL, and LILACS. A meta-analysis of the selected articles for the dynamic and static balance criteria was conducted in a population of older adults (over 65 years) with publications from 2010 to 2024. Results: Eighteen randomized clinical trials fulfilled the criteria. TCC improves dynamic balance in the timed up and go and gait speeds tests, and static balance in the single-leg test and functional reach test when compared with the control group in the meta-analysis. Adverse events were found in only one study, and the training parameters were heterogeneous. Conclusion: TCC improves older adults with both dynamic and static balance. The results of the parameters indicate a direction in which TCC is prescribed for clinical practice with minimal or no risk of adverse effects. [ABSTRACT FROM AUTHOR]

This study aimed to determine the effects of walking-only intervention (walking was the only exercise in which people participated) on physical function, fall-related outcomes, and health-related quality of life in community-dwelling older adults. We conducted a systematic search across five electronic databases, assessing risk of bias using Minds Manual for Guideline Development. Meta-analyses were performed, and pooled standardized mean differences were calculated. Nine studies (a total of 1,309 participants) were included, showing that walking-only interventions improved walking endurance (standardized mean difference: 1.11, 95% confidence interval: [0.08, 2.15]) and health-related quality of life (standardized mean difference: 0.71, 95% confidence interval: [0.18, 1.25]). However, there were no significant improvements in other outcomes. The certainty of the evidence based on the Grading of Recommendations, Assessment, Development, and Evaluation approach for all outcomes was graded as very low, primarily due to significant inconsistency and imprecision. Our results suggest that walking-only intervention can be effective for enhancing walking endurance and health-related quality of life for community-dwelling older adults. Further studies are required to investigate the effects of walking-only intervention. This need stems from the limited number of randomized controlled trials, heterogeneous intervention settings and results, and the very low certainty of the evidence. [ABSTRACT FROM AUTHOR]

BACKGROUND: For extended-release drug formulations, effective half-life (t 1/2eff ) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t 1/2eff of tacrolimus from these different formulations has not yet been assessed. The objective of this study was to characterize the t 1/2eff and terminal half-life (t 1/2z ) of an extended-release once-daily tacrolimus formulation (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). METHODS: A noncompartmental analysis of pharmacokinetic data obtained from a phase 2 study in de novo kidney transplant recipients receiving either LCPT or IR-Tac was conducted. Intensive blood sampling was performed on days 1, 7, and 14, and tacrolimus whole blood concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method. T 1/2eff was estimated using within-participant accumulation ratios. T 1/2z was estimated by linear regression of the terminal phase of the concentration versus time profile. RESULTS: The median accumulation ratios of LCPT and IR-Tac on day 14 were 3.18 and 2.06, respectively.The median (interquartile range; IQR) t 1/2eff for LCPT at day 14 of dosing was 48.4 (37.4-77.9) hours, whereas the t 1/2z was 20.3 (17.6-22.9) hours. For IR-Tac, the median (IQR) t 1/2eff and t 1/2z on day 14 were 12.5 (8.8-23.0) hours and 12.2 (9.2-15.7) hours, respectively. CONCLUSIONS: Consistent with its prolonged release of tacrolimus, LCPT demonstrated a higher accumulation ratio and a longer t 1/2eff compared with IR-Tac. These findings underscore the pharmacokinetic differences between different drug formulations of the same moiety and may help inform dose adjustments for LCPT in kidney transplantation.

OBJECTIVES: There is growing interest in assessing patient quality of life (QOL) following treatment of sinonasal tumors, including inverted papilloma (IP). We aimed to elucidate the natural history of postoperative QOL outcomes in IP patients treated with surgery. METHODS: Cases of sinonasal IP treated surgically at 4 tertiary academic rhinology centers were retrospectively reviewed. SNOT-22 scores were used to evaluate QOL preoperatively and postoperatively (1, 3, 6, 12 months). Repeated-measures ANOVA assessed for differences in mean scores over time. Linear regression identified factors associated with QOL longitudinally. RESULTS: 373 patients were analyzed. Mean preoperative SNOT-22 score was 20.6 ± 20.4, which decreased to 16.3 ± 18.8 (p = 0.041) and 11.8 ± 15.0 (p  0.05). When analyzed by SNOT-22 subdomains, nasal, sleep, and otologic/facial subdomain scores (all p  0.05). CONCLUSIONS: QOL outcomes related to IP resection are largely driven by nasal, sleep, and otologic/facial subdomains, though patients appear to experience enduring improvement as early as 3 months postoperatively. Recurrent disease is a major driver of negative QOL. LEVEL OF EVIDENCE: 4 Laryngoscope, 135:579-585, 2025.

BACKGROUND: Nonthermal, pulsed shortwave (radiofrequency) therapy (PSWT) is a nonpharmacologic, noninvasive modality that limited evidence suggests provides analgesia. Its potential favorable risk-benefit ratio stems from its lack of side effects and significant medical risks, applicability to any anatomic location, long treatment duration, and ease of application by simply affixing it with tape. Even with a relatively small treatment effect, PSWT might contribute to a multimodal analgesic regimen, similar to acetaminophen. However, widespread clinical use is hindered by a lack of systematic evidence. The current randomized, controlled pilot study was undertaken to determine the feasibility and optimize the protocol for a subsequent definitive investigation and estimate the treatment effect of PSWT on postoperative pain and opioid consumption. METHODS: Within the recovery room following primary knee and hip arthroplasty, cholecystectomy, hernia repair, and non-mastectomy breast surgery, we applied 1-3 PSWT devices (Model 088, BioElectronics Corporation, Frederick, Maryland) over the surgical bandages. Participants were randomized to 28 days of either active or sham treatment in a double-masked fashion. The outcomes of primary interest were the cumulative opioid consumption and the mean of the average and worst daily pain measured with the Numeric Rating Scale over the first 7 postoperative days. RESULTS: During the first 7 postoperative days, oxycodone consumption in participants given active treatment (n = 55) was a mean (SD) of 21 mg (24) versus 17 mg (26) in patients given sham (n = 57): difference 4 (95% CI, -5 to 13), p = 0.376. During this same period, the average daily pain intensity in patients given active treatment was 2.4 (1.6) versus 2.6 (1.7) in sham: difference -0.2 (95% CI -0.8 to 0.5), p = 0.597. Concurrently, the worst/maximum pain for the active group was 4.6 (2.0) versus 4.7 (2.1) in sham: difference -0.1 (95% CI -0.8 to 0.7), p = 0.888. No device-related systemic side effects or serious adverse events were identified. CONCLUSIONS: Pulsed shortwave (radiofrequency) therapy did not reduce pain scores and opioid requirements to a statistically significant or clinically relevant degree during the initial postoperative week in this pilot study. These results must be replicated with a subsequent study before being considered definitive. Data from this preliminary study may be used to help plan future trials.

Throughout the COVID-19 pandemic, underserved populations, such as racial and ethnic minority communities, were disproportionately impacted by illness and death. Ensuring people from diverse backgrounds have the ability to participate in clinical trials is key to advancing health equity. We sought to analyze the spatial variability in locations of COVID-19 trials sites and to test associations with demographic correlates. All available and searchable COVID-19 studies listed on ClinicalTrials.gov until 04/04/2022 and conducted in the United States were extracted at the trial-level, and locations were geocoded using the Microsoft Bing API. Publicly available demographic data were available at the county level for national analysis and the census tract level for local analysis. Independent variables included eight racial and ethnic covariates, both sexes, and twelve age categories, all of which were population-normalized. The county-level, population-normalized count of study site locations, by type, was used as the outcome for national analysis, thereby enabling the determination of demographic associations with geospatial availability to enroll as a participant in a COVID-19 study. Z-scores of the Getis-Ord Gi statistic were used as the outcome for local analysis in order to account for areas close to those with clinical study sites. For both national (p

Lewy bodies and neurofibrillary tangles, composed of α-synuclein (α-syn) and tau, respectively, often are found together in the same brain and correlate with worsening cognition. Human postmortem studies show colocalization of α-syn and tau occurs in Lewy bodies, but with limited effort to quantify colocalization. In this study, postmortem middle temporal gyrus tissue from decedents (n = 9) without temporal lobe disease (control) or with Lewy body disease (LBD) was immunofluorescently labeled with antibodies to phosphorylated α-syn (p-α-syn), tau phosphorylated at Ser202/Thr205 (p-tau), or exposure of taus phosphatase-activating domain (PAD-tau) as a marker of early tau aggregates. Immunofluorescence for major-histocompatibility complex class 2 (MHCII) and ionized calcium binding adaptor molecule 1 (Iba1) also was performed because inflammation is an additional pathological hallmark of LBDs, and they were a positive control for two markers known to colocalize. The abundance of p-α-syn, p-tau, and MHCII was significantly associated with diagnosis of LBD. Quantification of colocalization showed that MHCII and Iba1 colocalized, demonstrating activated immune cells are mostly microglia. However, p-α-syn rarely colocalized with p-tau or PAD-tau, although the overlap of p-α-syn with PAD-tau was significantly associated with LBD. In the rare cases pathologic α-syn and pathologic tau were found in the same Lewy body or Lewy neurite, tau appeared to surround α-syn but did not colocalize within the same structure. The relationship between tau and α-syn copathology is important for explaining clinical symptoms, severity, and progression, but there is no evidence for frequent, direct protein-protein interactions in the middle temporal gyrus.

BACKGROUND: Effective detection of cognitive impairment in the primary care setting is limited by lack of time and specialized expertise to conduct detailed objective cognitive testing and few well-validated cognitive screening instruments that can be administered and evaluated quickly without expert supervision. We therefore developed a model cognitive screening program to provide relatively brief, objective assessment of a geriatric patients memory and other cognitive abilities in cases where the primary care physician suspects but is unsure of the presence of a deficit. METHODS: Referred patients were tested during a 40-min session by a psychometrist or trained nurse in the clinic on a brief battery of neuropsychological tests that assessed multiple cognitive domains. Short questionnaires covering subjective cognitive complaints, symptoms of depression, and medical history were also administered. Results were conveyed to a dementia specialist who reviewed them and returned their judgement of the validity of the cognitive complaint to the primary care provider. Retrospective medical records review was carried out for a random (stratified) half of the sample to determine how screening results were utilized. Screening tests were repeated after two years in a subset of 69 patients. RESULTS: The 638 patients screened (mean age = 75.9 years; mean education = 14.9 years; 58% women) were classified by screening as having normal cognition (n = 177), depression (with possible cognitive changes; n = 115), mild cognitive impairment (MCI; n = 107), or dementia (n = 239). Classification accuracy was shown by high agreement with the eventual clinical diagnosis in the medical record (69%; Cohens Kappa = .38; p

BACKGROUND AND OBJECTIVES: Cerebrovascular reactivity (CVR) represents the ability of cerebral blood vessels to regulate blood flow in response to vasoactive stimuli and is related to cognition in cerebrovascular and neurodegenerative conditions. However, few studies have examined CVR in the medial temporal lobe, known to be affected early in Alzheimer disease and to influence memory function. We aimed to examine whether medial temporal CVR is associated with memory function in older adults with and without mild cognitive impairment (MCI). METHODS: In this observational study, independently living older adults free of dementia or stroke were recruited from the community and underwent brain MRI, neuropsychological assessment, and blood draw in an academic research setting. pCASL MRI quantified medial temporal lobe cerebral perfusion during CVR response to hypercapnia. Hypercapnia was induced by visually guided breathing exercises (15 seconds breath holds) during capnographic monitoring. MCI diagnosis and memory performance were assessed through comprehensive neuropsychological assessment. Aβ42/40 and pTau181 levels were quantified in blood plasma. Logistic and hierarchical linear regression examined medial temporal CVR in relation to MCI diagnosis and memory function. RESULTS: In a sample of 144 older adults (mean age = 69.6 years; SD = 7.4%; 34.7% male; mean education = 16.6 years, SD = 2.3), CVR to hypercapnia in the medial temporal lobe was attenuated in individuals with MCI after adjusting for age, sex, education, apolipoprotein ε4 carrier status, Aβ42/40 and pTau181 levels, and vascular risk factors (OR = 0.87, 95% CI [0.77-0.97], p = 0.013). Cerebrovascular reactivity to hypercapnia was associated with verbal memory performance for stories (B = 0.33, 95% CI [0.09-0.57], p = 0.009), a word list (B = 0.10, 95% CI [0.001-0.20], p = 0.048), and visual memory (B = 0.33, 95% CI [0.09-0.57], p = 0.008). DISCUSSION: Deficits in medial temporal CVR are observed in older adults with MCI and are related to worse memory function. Findings suggest that medial temporal cerebrovascular dysfunction is related to cognition and memory before the onset of dementia, independent of changes in Alzheimer pathophysiologic markers. Limitations of the study include the cross-sectional design. Future longitudinal studies are warranted to examine whether early cerebrovascular changes can predict progressive memory decline.

Existing air pollution metabolomics studies showed inconsistent results, often limited by small sample size and individual air pollutants effects. We conducted a metabolome-wide association study among 1096 women (68.2 ± 5.7 years) who provided blood samples (1998-2001) within the Cancer Prevention Study-II Nutrition Cohort. Annual average individual exposures to particulate matter, nitrogen dioxide, ozone, sulfur dioxide, and carbon monoxide in the year of blood draw were used. Metabolomics profiling was conducted on serum samples by Metabolon. We evaluated the individual air pollutants effects using multiple linear regression and the mixture effect using quantile g-computation, adjusting for confounders and false discovery rate (FDR). Ninety-five metabolites were significantly associated with at least one air pollutant or mixture (FDR < 0.05). These metabolites were enriched in pathways related to oxidative stress, systemic inflammation, energy metabolism, signals transduction, nucleic acid damage and repair, and xenobiotics. Sixty metabolites were confirmed with level 1 or 2 evidence, among which 21 have been previously linked to air pollution exposure, including taurine, creatinine, and sebacate. Overall, our results replicate prior findings in a large sample and provide novel insights into biological responses to long-term air pollution exposure using mixture analysis.

BackgroundDespite recent advances in the biology of IDH-wildtype glioblastoma, it remains a devastating disease with median survival of less than 2 years. However, the molecular underpinnings of the heterogeneous response to the current standard-of-care treatment regimen consisting of maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide remain unknown.MethodsComprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients was performed to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses.ResultsWhile TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (eg, EGFR, PTEN, and NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Furthermore, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation had shorter interval to recurrence and were significantly enriched in NF1, TP53, and RB1 alterations and the mesenchymal epigenetic class. Patients who developed somatic hypermutation following temozolomide treatment had significantly longer interval to disease recurrence and prolonged overall survival, and increased methylation at 4 specific CpG sites in the promoter region of MGMT was significantly associated with this development of hypermutation. Finally, an epigenomic evolution signature incorporating change in DNA methylation levels across 347 critical CpG sites was developed that significantly correlated with clinical outcomes.ConclusionsGlioblastoma undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.

Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and lower-middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A public sector manufacturer in Vietnam assessed the immunogenicity of NDV-HXP-S (COVIVAC) relative to an authorized vaccine. This phase 2 stage of a randomised, observer-blind, controlled, phase 1/2 trial was conducted at three community health centers in Thai Binh Province, Vietnam. Healthy males and non-pregnant females, 18 years of age and older, were eligible. Participants were randomised by age (18-59, ≥60 years) to receive one of three treatments by intramuscular injection twice, 28 days apart: COVIVAC at 3 μg or 6 μg, or AstraZeneca COVID-19 vaccine VAXZEVRIA™. Participants and personnel assessing outcomes were masked to treatment. The vaccine dose was selected based on Phase 1 results. A 6 μg dose was chosen to explore the immunogenicity gain over the 3-μg dose. The studys aim is to evaluate the safety and immunogenicity of COVIVAC at two dose levels compared to VAXZEVRIA, the most commonly used COVID-19 vaccine in Vietnam. The main outcome was the induction of 50% neutralising antibody titers against vaccine-homologous pseudotyped virus 14 days (day 43) and 6 months (day 197) after the second vaccination by age group. The primary immunogenicity and safety analyses included all participants who received one dose of the vaccine. ClinicalTrials.govNCT05940194. During August 10-23, 2021, 737 individuals were screened, and 374 were randomised (124-125 per group); all subjects received vaccine dose one and all but three received doses two four weeks later. Subjects 18-59 years of age achieved the following geometric mean titers of PNA 14 days after vaccine dose two: 153⋅28 (95 % CI 124·2-189⋅15) for COVIVAC 3 μg, 176⋅2 (95 % CI 141⋅45-220.27) for COVIVAC 6 μg, and 99⋅92(95 % CI 80.80-123⋅56) for VAXZEVRIA. Subjects ≥60 years of age also achieved potent geometric mean titers of PNA at the same timepoint: 183⋅57 (95 % CI 133.4-252⋅61) for COVIVAC 3 μg, 257⋅87 (95 % CI 181⋅6-367⋅18) for COVIVAC 6 μg, and 79⋅49(95 % CI 55⋅68-113⋅4) for VAXZEVRIA. On day 43, the geometric mean fold rise of 50 % neutralising antibody titers for subjects age 18-59 years was 31·20 (COVIVAC 3 μg N = 82, 95 % CI 25·14-38·74), 35·80 (COVIVAC 6 μg; N = 83, 95 % CI 29·03-44·15), 18·85 (VAXZEVRIA; N = 82, 95 % CI 15·10-23·54), and for subjects age ≥ 60 years was 37·27 (COVIVAC 3 μg; N = 42, 95 % CI 27·43-50·63), 50·10 (COVIVAC 6 μg; N = 40, 95 % CI 35·46-70·76), 16·11 (VAXZEVRIA; N = 40, 95 % CI 11·73-22·13). Among subjects seronegative for anti-S IgG at baseline, the day 43 geometric mean titer ratio of neutralising antibody (COVIVC 6 μg/VAXZEVRIA) was 1·77 (95 % CI 1·30-2·40) for subjects age 18-59 years and 3·24 (95 % CI 1·98-5·32) for subjects age ≥ 60 years. On day 197, the age-specific ratios were 1·11 (95 % CI 0·51-2·43) and 2·32 (0·69-7·85). Vaccines were well tolerated; reactogenicity was predominantly mild and transient. The percentage of subjects with unsolicited adverse events (AEs) during 28 days after vaccinations was similar among treatments (COVIVAC 3 μg 29·0 %, COVIVAC 6 μg 23·2 %, VAXZEVRIA 31·2 %); no vaccine-related AE was reported. Considering that induction of neutralising antibodies against SARS-CoV-2 has been correlated with the efficacy of COVID-19 vaccines, including VAXZEVRIA, our results suggest that vaccination with COVIVAC may afford clinical benefit matching or exceeding that of the VAXZEVRIA vaccine. ClinicalTrials.govNCT05940194.

BackgroundCancer survivors are at increased risk for cardiometabolic comorbidities following cancer treatment, which may be further exacerbated by cannabis and alcohol use. We aimed to examine the direct relationships of cannabis, alcohol, and the co-use of both substances with cardiometabolic risk factors and to explore disparities by race/ethnicity and sex.MethodsCross-sectional data were extracted from adult cancer survivors in the "All of Us" from 2018 to 2022. Cannabis use was defined as occasional or frequent/regular cannabis use (vs. never) in the past 3 months and hazardous alcohol intake (AUDIT-C >3 for females; AUDIT-C >4 for males) versus nonhazardous in the past year, respectively. Co-use was defined as participants who engaged in regular cannabis and hazardous alcohol intake. We identified binary cardiovascular, immune, and metabolic system biomarkers, with high values defined by clinically established cutoffs or >75th percentile. We used multivariable logistic regression adjusting for sociodemographic and clinical factors.ResultsIn our sample (N = 7,054), 7.6% were Hispanic, 6.2% were Black, and 86.2% were White cancer survivors. Less than 5% of Hispanic and White survivors reported substance co-use compared with 7% of Black survivors. Compared with never-users, co-users were 1.58 (95% confidence interval, 1.14-2.19) more likely to have high blood pressure. No significant associations were found between co-use and immune biomarkers or sex differences.ConclusionsCo-use of cannabis and hazardous alcohol may worsen high blood pressure in survivors, who are at higher risk for cardiometabolic comorbidities.ImpactThe study investigates substance use and cardiometabolic biomarkers, urging much research on their effects on cancer survivors.

BACKGROUND: Disease-modifying therapies targeting the diverse pathophysiology of Alzheimers disease (AD), including neuroinflammation, represent potentially important and novel approaches. The glucagon-like peptide-1 receptor agonist semaglutide is approved for the treatment of type 2 diabetes and obesity and has an established safety profile. Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms including neuroinflammatory, vascular, and other AD-related processes. Large randomized controlled trials are needed to assess the efficacy and safety of semaglutide in early-stage symptomatic AD. METHODS: evoke and evoke+ are randomized, double-blind, placebo-controlled phase 3 trials investigating the efficacy, safety, and tolerability of once-daily oral semaglutide versus placebo in early-stage symptomatic AD. Eligible participants were men or women aged 55-85 years with mild cognitive impairment or mild dementia due to AD with confirmed amyloid abnormalities (assessed by positron emission tomography or cerebrospinal fluid [CSF] analysis). After a maximum 12-week screening phase, an anticipated 1840 patients in each trial are randomized (1:1) to semaglutide or placebo for 156 weeks (104-week main treatment phase and 52-week extension). Randomized participants follow an 8-week dose escalation regimen (3 mg [weeks 0-4], 7 mg [weeks 4-8], and 14 mg [weeks 8-156]). The primary endpoint is the semaglutide-placebo difference on change from baseline to week 104 in the Clinical Dementia Rating - Sum of Boxes score. Analyses of plasma biomarkers, collected from all participants, and a CSF sub-study (planned n = 210) will explore semaglutide effects on AD biomarkers and neuroinflammation. RESULTS: Enrollment was undertaken between May 18, 2021, and September 8, 2023. Completion of the trials main phase is expected in September 2025, and the 52-week extension (in which participants and investigators remain blinded to treatment assignment) will continue to October 2026. CONCLUSION: evoke and evoke+ are the first large-scale trials to investigate the disease-modifying potential of semaglutide in participants with early-stage symptomatic AD, including exploration of effects on AD biomarkers and neuroinflammation. The trials will provide data on the potential disease-modifying effects of semaglutide and will be important in evaluating its utility in the treatment of early-stage symptomatic AD. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04777396 and NCT04777409. Date: 02/03/2021.

BACKGROUNDS: Digital, online assessments are efficient means to detect early cognitive decline, but few studies have investigated the relationship between remotely collected subjective cognitive change and cognitive decline. We hypothesized that the Everyday Cognition Scale (ECog), a subjective change measure, predicts longitudinal change in cognition in the Brain Health Registry (BHR), an online registry for neuroscience research. METHODS: This study included BHR participants aged 55 + who completed both the baseline ECog and repeated administrations of the CANTAB® Paired Associates Learning (PAL) visual learning and memory test. Both self-reported ECog (Self-ECog) and study partner-reported ECog (SP-ECog), and two PAL scores (first attempt memory score [FAMS] and total errors adjusted [TEA]) were assessed. We estimated associations between multiple ECog scoring outputs (ECog positive [same or above cut-off score], ECog consistent [report of consistent decline in any item], and total score) and longitudinal change in PAL. Additionally we assessed the ability of ECog to identify decliners, who exhibited the worst PAL progression slopes corresponding to the fifth percentile and below. RESULTS: Participants (n = 16,683) had an average age of 69.07 ± 7.34, 72.04% were female, and had an average of 16.66 ± 2.26 years of education. They were followed for an average of 2.52 ± 1.63 visits over a period of 11.49 ± 11.53 months. Both Self-ECog positive (estimate = -0.01, p

Brain inflammation, with an increased density of microglia and macrophages, is an important component of Alzheimer's disease and a potential therapeutic target. However, it is incompletely characterized, particularly in patients whose disease begins before the age of 65 years and, thus, have few co-pathologies. Inflammation has been usefully imaged with translocator protein (TSPO) PET, but most inflammation PET tracers cannot image subjects with a low-binder TSPO rs6971 genotype. In an important development, participants with any TSPO genotype can be imaged with a novel tracer, 11C-ER176, that has a high binding potential and a more favourable metabolite profile than other TSPO tracers currently available. We applied 11C-ER176 to detect brain inflammation in mild cognitive impairment (MCI) caused by early-onset Alzheimer's disease. Furthermore, we sought to correlate the brain localization of inflammation, volume loss, elevated amyloid-β (Aβ)and tau. We studied brain inflammation in 25 patients with early-onset amnestic MCI (average age 59 ± 4.5 years, 10 female) and 23 healthy controls (average age 65 ± 6.0 years, 12 female), both groups with a similar proportion of all three TSPO-binding affinities. 11C-ER176 total distribution volume (VT), obtained with an arterial input function, was compared across patients and controls using voxel-wise and region-wise analyses. In addition to inflammation PET, most MCI patients had Aβ (n = 23) and tau PET (n = 21). For Aβ and tau tracers, standard uptake value ratios were calculated using cerebellar grey matter as region of reference. Regional correlations among the three tracers were determined. Data were corrected for partial volume effect. Cognitive performance was studied with standard neuropsychological tools. In MCI caused by early-onset Alzheimer's disease, there was inflammation in the default network, reaching statistical significance in precuneus and lateral temporal and parietal association cortex bilaterally, and in the right amygdala. Topographically, inflammation co-localized most strongly with tau (r = 0.63 ± 0.24). This correlation was higher than the co-localization of Aβ with tau (r = 0.55 ± 0.25) and of inflammation with Aβ (0.43 ± 0.22). Inflammation co-localized least with atrophy (-0.29 ± 0.26). These regional correlations could be detected in participants with any of the three rs6971 TSPO polymorphisms. Inflammation in Alzheimer's disease-related regions correlated with impaired cognitive scores. Our data highlight the importance of inflammation, a potential therapeutic target, in the Alzheimer's disease process. Furthermore, they support the notion that, as shown in experimental tissue and animal models, the propagation of tau in humans is associated with brain inflammation.