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High-density lipoprotein (HDL) is protective against cardiovascular disease. Exercise can increase HDL concentration, and some evidence suggests that this effect occurs more strongly in women than in men. Both HDL and exercise are associated with inflammation. We hypothesized a sex-by-exercise interaction on HDL level, whereby women would benefit from exercise more strongly than men, and tumor necrosis factor alpha and serum soluble tumor necrosis factor receptor-2 would mediate this relationship. This study included 2,957 older adult participants (1,520 women; 41% Black, 59% White; 73.6-years-old) from the Health, Aging, and Body Composition study. Regression models revealed a positive exercise-HDL relationship in women only (sex-by-exercise interaction: β = 0.09, p =.013; exercise on HDL in women: β = 0.07, p =.015), mediated by TNFα (axb = 0.15; CI: 0.01, 0.30), suggesting that exercise may increase HDL levels in women through reduced inflammation. Given that vascular risk contributes to Alzheimer's disease risk, findings have implications for sex differences in AD risk factors. [ABSTRACT FROM AUTHOR]

Background: Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. Objective: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. Methods: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. Conclusion: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. Trial registration: ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360. [ABSTRACT FROM AUTHOR]

Background: Studies have reported higher plasma matrix metalloproteinase-9 (MMP-9) levels in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Despite evidence that MMP-9 activity and its influence on AD pathophysiology may be modulated by sex hormones, sex differences in the association between MMP-9 and AD biomarkers and cognition have not been explored. Methods: Our sample included 238 amyloid-β (Aβ)-positive participants with MCI or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (37.4% women, 74.6 ± 7.3 years). We used linear regression models to examine whether sex modified free and total plasma MMP-9 associations with CSF t-tau, p-tau181, and Aβ42. We used linear mixed effects models to examine whether sex modified total and free plasma MMP-9 associations with cognition, using longitudinal Mini-Mental Status Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) data. Results: Total and free MMP-9 levels did not differ by sex, but AD dementia patients had higher total MMP-9 levels than participants with MCI (β = 0.06 [−0.11 to −0.01], p = 0.031). Sex modified the association of CSF t-tau with total (β = 128.68 [55.37 to 201.99], p < 0.001) and free MMP-9 (β = 98.61 [33.61 to 163.62], p = 0.003), whereby higher total and free MMP-9 correlated with higher CSF t-tau in women and lower CSF t-tau in men. Higher free MMP-9 correlated with lower CSF p-tau181 among men (β = −14.98 [−27.37 to −2.58], p = 0.018), but not women. In participants with MCI, higher free MMP-9 levels were associated with higher CSF Aβ42 among men (β = 26.88 [4.03 to 49.73], p = 0.022) but not women. In the overall sample, higher free and total MMP-9 at baseline predicted worsening MMSE scores in women (β = −2.10 [−3.97 to −0.27], p = 0.027 and β = −2.24 [−4.32 to −0.18], p = 0.035) but not men. Higher free MMP-9 correlated with worse ADAS-cog scores (β = 12.34 [3.02 to 21.65], p = 0.011) in women (β = 12.34 [3.02 to 21.65], p = 0.011) but not men with AD dementia cross-sectionally but correlated with worsening ADAS-cog scores longitudinally only in men (β = 8.98 [0.27 to 17.68], p = 0.042). Conclusions: MMP-9 may have more detrimental effects on AD-related pathological and cognitive changes in women. If replicated, our findings could help uncover potential mechanisms contributing to women's elevated susceptibility to AD. [ABSTRACT FROM AUTHOR]

Objective: Primary age-related tauopathy (PART) refers to tau neurofibrillary tangles restricted largely to the medial temporal lobe in the absence of significant beta-amyloid plaques. PART has been associated with cognitive impairment, but contributions from concomitant limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) are underappreciated.Methods: We compare prevalence of LATE-NC and vascular copathologies in age- and Braak-matched patients with PART (n = 45, Braak stage I-IV, Thal phase 0-2) or early stage Alzheimer disease neuropathologic change (ADNC; n = 51, Braak I-IV, Thal 3-5), and examine their influence on clinical and cognitive decline.Results: Concomitant LATE-NC and vascular pathology were equally common, and cognition was equally impaired, in PART (Mini-Mental State Examination [MMSE] = 24.8 ± 6.9) and ADNC (MMSE = 24.2 ± 6.0). Patients with LATE-NC were more impaired than those without LATE-NC on the MMSE (by 5.8 points, 95% confidence interval [CI] = 3.0-8.6), Mattis Dementia Rating Scale (DRS; 17.5 points, 95% CI = 7.1-27.9), Clinical Dementia Rating, sum of boxes scale (CDR-sob; 5.2 points, 95% CI = 2.1-8.2), memory composite (0.8 standard deviations [SD], 95% CI = 0.1-1.6), and language composite (1.1 SD, 95% CI = 0.2-2.0), and more likely to receive a dementia diagnosis (odds ratio = 4.8, 95% CI = 1.5-18.0). Those with vascular pathology performed worse than those without on the DRS (by 10.2 points, 95% CI = 0.1-20.3) and executive composite (1.3 SD, 95% CI = 0.3-2.3). Cognition declined similarly in PART and ADNC over the 5 years preceding death; however, LATE-NC was associated with more rapid decline on the MMSE (β = 1.9, 95% CI = 0.9-3.0), DRS (β = 7.8, 95% CI = 3.4-12.7), CDR-sob (β = 1.9, 95% CI = 0.4-3.7), language composite (β = 0.5 SD, 95% CI = 0.1-0.8), and vascular pathology with more rapid decline on the DRS (β = 5.2, 95% CI = 0.6-10.2).Interpretation: LATE-NC, and to a lesser extent vascular copathology, exacerbate cognitive impairment and decline in PART and early stage ADNC. ANN NEUROL 2022;92:425-438. [ABSTRACT FROM AUTHOR]

The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer's pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer's disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer's disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-β42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-β42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer's disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer's disease progression. [ABSTRACT FROM AUTHOR]

We have previously derived power calculation formulas for cohort studies and clinical trials using the longitudinal mixed effects model with random slopes and intercepts to compare rate of change across groups [Ard & Edland, Power calculations for clinical trials in Alzheimer's disease. J Alzheim Dis 2011;21:369–77]. We here generalize these power formulas to accommodate 1) missing data due to study subject attrition common to longitudinal studies, 2) unequal sample size across groups, and 3) unequal variance parameters across groups. We demonstrate how these formulas can be used to power a future study even when the design of available pilot study data (i.e., number and interval between longitudinal observations) does not match the design of the planned future study. We demonstrate how differences in variance parameters across groups, typically overlooked in power calculations, can have a dramatic effect on statistical power. This is especially relevant to clinical trials, where changes over time in the treatment arm reflect background variability in progression observed in the placebo control arm plus variability in response to treatment, meaning that power calculations based only on the placebo arm covariance structure may be anticonservative. These more general power formulas are a useful resource for understanding the relative influence of these multiple factors on the efficiency of cohort studies and clinical trials, and for designing future trials under the random slopes and intercepts model. [ABSTRACT FROM AUTHOR]

Coupled with aging, chronic stress experienced by dementia caregivers often leads to deteriorating health. Comparing caregivers and non-caregivers, we tested whether depression and loneliness mediate the relationship between caregiver status and a measure of chronic stress, the Perceived Stress Scale. Seventy-six cognitively normal older adults (mean age 72.7) were identified as caregivers or non-caregivers based on the functional independence of a paired family member. Caregivers reported more perceived stress, depression, and loneliness than non-caregivers. Using multiple mediation analyses, we found that loneliness and depression mediated the relationship of caregiver status with perceived stress. The loneliness effect on perceived stress was both direct and via its relationship with depressive symptoms. The findings suggest loneliness as a likely point of intervention to reduce caregiver stress. Initiatives to enable caregivers to maintain or develop social relationships apart from caregiver responsibilities may mitigate stress and its negative impact on mental and physical health. [ABSTRACT FROM AUTHOR]

Introduction: Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) are characterized by cognitive alterations, visual hallucinations, and motor impairment. Diagnosis is based on type and timing of clinical manifestations; however, determination of clinical subtypes is challenging. The utility of blood DNA methylation as a biomarker for Lewy body disorders (LBD) is mostly unexplored. Methods: We performed a cross-sectional analysis of blood methylation in 42 DLB and 50 PDD cases applying linear models to compare groups and logistic least absolute shrinkage and selection operator regression to explore the discriminant power of methylation signals. Results: DLB blood shows differential methylation compared to PDD. Some methylation changes associate with core features of LBD. Sets of probes show high predictive value to discriminate between variants. Discussion: Our study is the first to explore LBD blood methylation. Despite overlapping clinical presentation, we detected differential epigenetic signatures that, if confirmed in independent cohorts, could be developed into useful biomarkers. [ABSTRACT FROM AUTHOR]

Background: Growing awareness of Alzheimer's disease (AD) has prompted a demand for quick and effective ways to screen for memory loss and cognitive decline in large numbers of individuals in the community. Periodic Memory Screening Day events provide free, brief cognitive screening aimed at those 65 years and older, and can serve as an opportunity to gauge participants' attitudes towards AD research and recruit them into ongoing research projects. Methods: Over 6 single-day events in 2 years, more than 574 individuals were individually screened using the MoCA and a story recall task (immediate and delayed), given feedback about their performance, and introduced to AD research and opportunities to participate. Results: Screening classified 297 individuals (52.0%) as having "No Decline," 192 (33.6%) as "Possible decline," and 82 (14.4%) as "Likely decline." Those with "Likely decline" were older and less educated, had more memory concerns, were more likely to be men, and were less likely to have a positive family history of dementia than those with "No Decline." Subsequent validation of screening procedures against a full clinical evaluation showed 72% classification accuracy with a skew towards over-calling Possible and Likely decline and thereby guiding questionable individuals to a more thorough evaluation. Of those screened, 378 (66%) agreed to additional research and consented to being listed in a research registry, and a majority (70–85%) of those consenting reported they were amenable to various AD research procedures including lumbar puncture, MRI, and autopsy. Overall, 19.1% of those screened met inclusion criteria for ongoing studies and were successfully recruited into AD research. Conclusions: Conducting a few concentrated community memory screening events each year may help meet the public's demand for brief assessment of memory concerns and can be a relatively effective and efficient recruitment strategy for AD research. [ABSTRACT FROM AUTHOR]

Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1+/−) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography–mass spectrometry (LC–MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC–MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions. [ABSTRACT FROM AUTHOR]

Background: Findings are inconsistent regarding the role of traumatic head injury in the subsequent development of neurologic outcomes.Objective: Examine the relationship between head injury and later cognitive impairment.Methods: A sample of 3,123 Japanese-American men was assessed for history of head injury and evaluated for cognitive impairment using the Cognitive Abilities Screening Instrument (CASI). For a subsample of 676 respondents, neuropathologic results from those with and without head injury were compared.Results: Although the crude model showed an association between history of head injury and later severe cognitive impairment, the relationship lost significance in the adjusted model (OR = 1.320, CI: 0.90-1.93), regardless of time between injury and impairment. Similar to cognitive impairment, hippocampal sclerosis was observed significantly more in the brains of respondents with a history of head injury in the crude model, but the relationship weakened in the adjusted model (OR = 1.462, CI: 0.68-3.12). After adjustment, decedents with a head injury demonstrated marginally higher brain weight (OR = 1.003, CI: 1.00-1.01).Conclusion: We did not find a relationship between head injury and subsequent cognitive decline in this cohort. The neuropathology results also displayed no strong association between history of head injury and specific brain lesions and characteristics. These results support other findings in prospective cohorts. However, they could be influenced by the demographic make-up of the sample (male Japanese-Americans) or by the observation that the majority reported only a single head injury. [ABSTRACT FROM AUTHOR]

Introduction: The CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) dementia risk score is based on demographic, genetic, and modifiable risk factors in midlife and has been shown to be predictive of later-life dementia. Objective: To test the predictive capacity of the CAIDE dementia risk score among a cohort of Japanese-American men. Methods: Midlife measures were obtained from a sample of 3,582 Japanese-American men in the Honolulu Heart Program (1965–1968, average age = 53.1 years). A follow-up exam in 1991 (average age = 77.8 years) assessed cognitive impairment using the Cognitive Abilities Screening Instrument (CASI). Severe cognitive impairment was defined as a CASI score <60. Results: In this cohort, the CAIDE dementia risk score demonstrates significant association with later-life severe cognitive impairment (OR = 1.477, 95% CI: 1.39–1.58). However, the area under the receiver-operating characteristic curve c-statistics suggests poor predictive ability (c = 0.645, 95% CI: 0.62–0.67). Using a score cut-point of 10, the accuracy is acceptable (0.82), but the sensitivity is low (0.50). Conclusion: While the CAIDE dementia risk score at midlife is associated with later development of cognitive impairment in Japanese-American men, its predictive capacity in this population is weak. [ABSTRACT FROM AUTHOR]

Parkinson's Disease (PD) is a common neurodegenerative disorder currently diagnosed based on the presentation of characteristic movement symptoms. Unfortunately, patients exhibiting these symptoms have already undergone significant dopaminergic neuronal loss. Earlier diagnosis, aided by molecular biomarkers specific to PD, would improve overall patient care. Epigenetic mechanisms, which are modified by both environment and disease pathophysiology, are emerging as important components of neurodegeneration. Alterations to the PD methylome have been reported in epigenome-wide association studies. However, the extent to which methylation changes correlate with disease progression has not yet been reported; nor the degree to which methylation is affected by PD medication. We performed a longitudinal genome-wide methylation study surveying ~850,000 CpG sites in whole blood from 189 well-characterized PD patients and 191 control individuals obtained at baseline and at a follow-up visit ~2 y later. We identified distinct patterns of methylation in PD cases versus controls. Importantly, we identified genomic sites where methylation changes longitudinally as the disease progresses. Moreover, we identified methylation changes associated with PD pathology through the analysis of PD cases that were not exposed to anti-parkinsonian therapy. In addition, we identified methylation sites modulated by exposure to dopamine replacement drugs. These results indicate that DNA methylation is dynamic in PD and changes over time during disease progression. To the best of our knowledge, this is the first longitudinal epigenome-wide methylation analysis for Parkinson's disease and reveals changes associated with disease progression and in response to dopaminergic medications in the blood methylome. [ABSTRACT FROM AUTHOR]

Background/Aims: Mild cognitive impairment (MCI) lacks a "gold standard" operational definition. The Jak/Bondi actuarial neuropsychological criteria for MCI are associated with improved diagnostic stability and prediction of progression to dementia compared to conventional MCI diagnostic approaches, although its utility in diagnosing MCI in old-old individuals (age 75+) is unknown. Therefore, we investigated the applicability of neuropsychological MCI criteria among old-old from the Framingham Heart Study. Methods: A total of 347 adults (ages 79–102) were classified as cognitively normal or MCI via Jak/Bondi and conventional Petersen/Winblad criteria, which differ on cutoffs for cognitive impairment and number of impaired scores required for a diagnosis. Cox models examined MCI status in predicting risk of progression to dementia. Results: MCI diagnosed by both the Jak/Bondi and Petersen/Winblad criteria was associated with incident dementia; however, when both criteria were included in the regression model together, only the Jak/Bondi criteria remained statistically significant. At follow-up, the Jak/Bondi criteria had a lower MCI-to-normal reversion rate than the Petersen/Winblad criteria. Conclusions: Our findings are consistent with previous research on the Jak/Bondi criteria and support the use of a comprehensive neuropsychological diagnostic approach for MCI among old-old individuals. [ABSTRACT FROM AUTHOR]

Clinical, neuropsychological, and neurological procedures used to diagnose Alzheimer's disease (AD) and related dementias were largely developed and validated in well-educated, non-Latino, English-speaking populations. Sociocultural and genetic differences in Latinos might influence the accuracy of clinical diagnosis of AD and other dementias. We aim to compare the accuracy of the clinical diagnosis of AD and related dementias in Latinos with the corresponding neuropathological diagnosis. From the UCSD Alzheimer's Disease Research Center longitudinal cohort, we selected all Latino participants who had autopsy neuropathological studies from 1991 to 2017. Participants underwent annual neurological clinical evaluations, standard neuropsychological tests, neuroimaging, and genotyping of Apolipoprotein E. We calculated the sensitivity and specificity of the clinical diagnosis of AD against the primary pathological diagnosis. Of the 34 participants with a primary neuropathological diagnosis of AD, 33 (97.1%) were correctly clinically diagnosed as having AD at the last clinical evaluation, and 1 was incorrectly diagnosed with dementia with Lewy bodies. Of the 19 participants without a primary neuropathological diagnosis of AD, 8 were incorrectly clinically diagnosed with probable AD at the last clinic evaluation. The clinical diagnosis of AD at the last clinical evaluation had 97.1% sensitivity and 57.9% specificity for autopsy-verified AD. In this Latino cohort, clinicians predicted AD pathological findings with high sensitivity but moderate specificity. Tangle-only dementia was the most common misdiagnosis. Our study suggests that current procedures and instruments to clinically determine AD in Latinos have high sensitivity compared with neuropathology, but specificity needs to be improved. [ABSTRACT FROM AUTHOR]

Transactive response binding protein-43 (TDP-43) cytoplasmic neuronal and glial aggregates (pathologic TDP-43) have been described in multiple brain diseases. We describe the associations between neuropathologically confirmed TDP-43 and cognition in two population-based cohorts: the Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS). In the HAAS, there was a significant association between hippocampal sclerosis (HS) and TDP-43 (OR = 11.04, p < 0.0001, 95% CI 3.57-34.13). In the NS, there were significant associations between TDP-43 and HS (OR = 16.44, p > 0.001 95%, CI 7.10-38.00) and Alzheimer's disease (AD) severity (OR = 1.74, p = 0.009, 95% CI 1.15-2.64). When cognitive scores were added to the model, HS remained significant but the other variables were not. When HS was removed from the model, the overall model remained significant and the associations between cognitive performance and TDP-43 (OR = 2.11, p = 0.022, 95% CI 1.11-4.02) were significant. In the NS, there was a significant association between cognitive performance and TDP-43 (OR 1.94 p = 0.005, 95% CI 1.22-3.09) (HS remained significant, but AD did not). When HS was removed from the model, only CERAD was significant (OR = 2.43 p < 0.001, 95% CI 1.58-3.74). These results support a consistent association between pathologic TDP-43, HS, and the development of cognitive impairment in two large studies of brain aging, while the relationship between AD pathology and TDP-43 may vary according to cohort-specific features. [ABSTRACT FROM AUTHOR]

Clinical trials of chronic, progressive conditions use rate of change on continuous measures as the primary outcome measure, with slowing of progression on the measure as evidence of clinical efficacy. For clinical trials with a single prespecified primary endpoint, it is important to choose an endpoint with the best signal-to-noise properties to optimize statistical power to detect a treatment effect. Composite endpoints composed of a linear weighted average of candidate outcome measures have also been proposed. Composites constructed as simple sums or averages of component tests, as well as composites constructed using weights derived from more sophisticated approaches, can be suboptimal, in some cases performing worse than individual outcome measures. We extend recent research on the construction of efficient linearly weighted composites by establishing the often overlooked connection between trial design and composite performance under linear mixed effects model assumptions and derive a formula for calculating composites that are optimal for longitudinal clinical trials of known, arbitrary design. Using data from a completed trial, we provide example calculations showing that the optimally weighted linear combination of scales can improve the efficiency of trials by almost 20% compared with the most efficient of the individual component scales. Additional simulations and analytical results demonstrate the potential losses in efficiency that can result from alternative published approaches to composite construction and explore the impact of weight estimation on composite performance. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background Heightened stigma surrounding the action of smoking may decrease the likelihood that individuals who engage in smoking identify with the label 'smoker'. Non-identifying smokers (NIS) may undermine accurate smoking prevalence estimates and can be overlooked by tobacco control efforts. Objective We sought to characterise NIS in a cross-sectional study using a sample representative of the population of adults (>18 years) in California who reported smoking at least 100 cigarettes in their lifetime, smoking at least some days and at least once in the last 30 days (n=1698). Individuals were considered NIS if they met the above criteria and answered 'no' when asked if they 'considered themselves a smoker'. Results We estimate that 395 928 (SD=54 126) NIS were living in California in 2011 (a prevalence of 12.3% of all smokers in California). The odds of being NIS were higher among non-daily smokers who were previously daily smokers (adjusted OR (AOR)=7.63, 95% CI 2.67 to 21.8) or were never previously daily smokers (AOR=7.14, CI 2.78 to 18.3) compared with daily smokers. The odds of being an NIS were also higher among those who did not believe they were addicted to cigarettes (AOR=3.84, CI 1.68 to 9.22), were older than 65 years (vs less than 45 years) (AOR=3.35, CI 1.16 to 9.75) or were from ethnic minorities including Black and Asian (vs non-Hispanic white) (AOR=3.16, CI 1.19 to 8.49). Conclusions Smoking surveillance should restructure selection criteria to more accurately account for NIS in areas with high stigma toward smokers. Targeted interventions may be needed for NIS including educating healthcare providers to enquire more deeply into smoking habits. [ABSTRACT FROM AUTHOR]

Objectives: Our objective was to determine if the quality of care of diabetic patients at a Student-Run Free Clinic Project (SRFCP) meets the standard of care, is comparable with other published outcomes, and whether pertinent diabetic clinical indicators improve over time.Methods: The authors conducted a retrospective chart review of diabetic patients at three University of California-San Diego (UCSD) SRFCP sites from December 1, 2008 to December 1, 2009 (n=182), calculated the percentage who received recommended screening tests, percent at goal, and compared these to published outcomes using Fisher's exact tests. Baseline measures were compared to most recent values using paired t tests.Results: The percentage of patients who received recommended screening tests (process measures) was blood pressure (BP) 100%, HbA1c 99.5%, creatinine 99.5%, LDL 93%, HDL and triglycerides 88%, microalbumin/creatinine ratio 80%, and ophthalmology exam 32%. Intermediate outcomes included: 70% of patients were at LDL goal <100, 70% had microalbumin/creatinine ratio <30, 61% of males were at HDL goal %gt;40, 47% of females at HDL goal>50, 52% with triglycerides <150, 45% had BP <130/80, and 30% of patients had HbA1c <7. Mean HbA1c, LDL, HDL, triglycerides and blood pressure improved significantly over time.Conclusions: Diabetic patients at UCSD SRFCP reached goals for both process measures and intermediate outcomes at rates that meet or exceed published outcomes of insured and uninsured diabetics on nearly all measures, with the exception of ophthalmology screening. Glycemic control, cholesterol levels, and blood pressure improved significantly during care at the UCSD SRFCP. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Our objective was to determine if the quality of care of diabetic patients ata Student-Run Free Clinic Project (SRFCP) meets the standard of care, is comparable with other published outcomes, and whether pertinent diabetic clinical indicators improve overtime. METHODS: The authors conducted a retrospective chart review of diabetic patients at three University of California-San Diego (UCSD) SRFCP sites from December 1, 2008 to December 1, 2009 (n=182), calculated the percentage who received recommended screening tests, percent at goal, and compared these to published outcomes using Fisher's exact tests. Baseline measures were compared to most recent values using paired t tests. RESULTS: The percentage of patients who received recommended screening tests (process measures) was blood pressure (BP) 100%, HbAlc 99.5%, creatinine 99.5%, LDL 93%, HDL and triglycerides 88%, microalbumin/creatinine ratio 80%, and ophthalmology exam 32%. Intermediate outcomes included: 70% of patients were at LDL goal <100, 70% had microalbumin/ creatinine ratio <30, 61% of males were at HDL goal >40, 47% of females at HDL goal>50, 52% with triglycerides <150, 45% had BP <130/80, and 30% of patients had HbAlc <7. Mean HbAlc, LDL, HDL, triglycerides and blood pressure improved significantly over time. CONCLUSIONS: Diabetic patients at UCSD SRFCP reached goals for both process measures and intermediate outcomes at rates that meet or exceed published outcomes of insured and uninsured diabetics on nearly all measures, with the exception of ophthalmology screening. Glycemic control, cholesterol levels, and blood pressure improved significantly during care at the UCSD SRFCP. [ABSTRACT FROM AUTHOR]

Objectives: Little is currently known about price sensitivity across ethnic groups as well as for non-daily smokers. To address this issue, this study compared perceived price sensitivity across smoking status (daily and non-daily) and within ethnicity (Hispanic and non-Hispanic White) in a recent representative population survey of California smokers. Methods: This study employed data from the 2008 California Tobacco Survey (CTS), a large population-based random-digit-dialed telephone survey. Participants were 1,777 non-Hispanic White and 450 Hispanic respondents who had smoked at least 100 cigarettes and currently smoked daily or on some days. Results: Differences in perceived price sensitivity were found by ethnicity when controlling for age, gender, and cigarette consumption. Comparisons across ethnic groups indicated that Hispanic smokers, in general, have more price-sensitive perceptions than non-Hispanic White smokers. However, daily versus non-daily status had no effect on price sensitivity when controlling for cigarette quantity. Conclusions: These findings indicate that pricing increases may be differentially influential for Hispanic compared with non-Hispanic White smokers across smoking status categories. [ABSTRACT FROM PUBLISHER]

Purpose: A knowledge gap exists between general physicians and specialists in diagnosing and managing Alzheimer disease (AD). This gap is concerning due to the estimated rise in prevalence of AD and cost to the health care system. Medical school is a viable avenue to decrease the gap, educating future physicians before they specialize. The purpose of this study was to assess the knowledge level of students in their first and final years of medical school. Methods: Fourteen participating United States medical schools used e-mail student rosters to distribute an online survey of a quantitative cross-sectional assessment of knowledge about AD; 343 students participated. Knowledge was measured using the 12-item University of Alabama at Birmingham AD Knowledge Test for Health Professionals. General linear models were used to examine the effect of demographic variables and previous experience with AD on knowledge scores. Results: Only 2.5% of first year and 68.0% of final year students correctly scored ten or more items on the knowledge scale. Personal experience with AD predicted higher knowledge scores in final year students (P=0.027). Conclusion: Knowledge deficiencies were common in final year medical students. Future studies to identify and evaluate the efficacy of AD education programs in medical schools are warranted. Identifying and disseminating effective programs may help close the knowledge gap. [ABSTRACT FROM AUTHOR]

Purpose: Age-related macular degeneration (AMD) is the leading cause of incurable vision loss in older adults in industrialized countries and is on a trajectory to disable a growing number of persons as societies age. To assess the potential of using telemedicine for expansion of an in-person AMD self-management program, we examined the extent of computer use in a sample of older adults with AMD. Methods: 160 older adult volunteers (mean age = 76 years; female = 51%) with AMD (mean visual acuity in better eye: 20/40; worse eye: 20/90) were randomly selected from members of the San Diego County AMD Registry. Computer use was assessed with a Health and Impact Questionnaire. Dependent measures were Snellen visual acuity, National Eye Institute-Visual Function Questionnaire, the AMD Self-Efficacy Questionnaire, and the Geriatric Depression Scale. Results: Overall 70.6% reported computer use at least once per month. By age and gender stratum, 76.5% of men aged 60-74 years, 73.3% of men aged 75 years and over, 74.3% of women aged 60-74 years, and 60.9% of women aged 75 years and over used computers. In logistic regression analyses controlling for age and gender, computer use was associated with better visual acuity ( P = 0.029), higher education ( P = 0.002), and self-efficacy for communication ( P = 0.027). Conclusion: The majority of older adults with AMD in our sample used computers, with use highest among more educated and visually intact patients. Computer use to access the Internet is feasible in AMD patients and should be encouraged. The inclusion of computer use in measures of AMD-related functioning appears warranted. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a triplet-repeat, CAG expansion mutation. Although CAG repeat length is thought to correlate with pathologic burden and disease severity, considerable variability in clinical phenotype remains. This study examined whether neuropathologic burden at autopsy corresponded with severity of clinical phenotype in HD. The brains of 24 patients with a clinical and genetic diagnosis of HD were analyzed at autopsy. Subjects were stratified on the basis of Vonsattel staging as mild/moderate (stage 1-2; n = 7) or severe (stage 3-4; n = 17). Clinical severity was assessed on the basis of the Mini-Mental State Examination (MMSE; 0-30) and two Unified Huntington's Disease Rating Scale (UHDRS) functional components: the Independence Scale (10-100) and the Total Functional Capacity (0-13). Mild/moderate subjects were significantly older, had lower CAG repeat lengths, and greater fixed brain weights than those classified as severe. Patients who were pathologically classified as severe at autopsy were, on average, younger at age of onset and death and less well educated. Despite obvious clinical and pathological differences between mild-moderate and severe HD subjects at autopsy, mean MMSE scores of the two groups before death were surprisingly similar. Correlations between Vonsattel stage and functional assessment scores before death were low and not statistically significant. Our results suggest that the extent of striatal changes in HD may not always correlate with clinical disease severity as measured by UHDRS functional scales. © 2012 Movement Disorder Society [ABSTRACT FROM AUTHOR]

The downstream targets of amyloid β (Aβ)-oligomers remain elusive. One hypothesis is that Aβ-oligomers interrupt axonal transport. Although previous studies have demonstrated Aβ-induced transport blockade, early effects of low-n soluble Aβ-oligomers on axonal transport remain unclear. Furthermore, the cargo selectivity for such deficits (if any) or the specific effects of Aβ on the motility kinetics of transported cargoes are also unknown. Toward this, we visualized axonal transport of vesicles in cultured hippocampal neurons treated with picomolar ( p m) levels of cell-derived soluble Aβ-oligomers. We examined select cargoes thought to move as distinct organelles and established imaging parameters that allow organelle tracking with consistency and high fidelity - analyzing all data in a blinded fashion. Aβ-oligomers induced early and selective diminutions in velocities of synaptic cargoes but had no effect on mitochondrial motility, contrary to previous reports. These changes were N-methyl d-aspartate receptor/glycogen synthase kinase-3β dependent and reversible upon washout of the oligomers. Cluster-mode analyses reveal selective attenuations in faster-moving synaptic vesicles, suggesting possible decreases in cargo/motor associations, and biochemical experiments implicate tau phosphorylation in the process. Collectively, the data provide a biological basis for Aβ-induced axonal transport deficits. [ABSTRACT FROM AUTHOR]