Multiverse analysis and the Bradley-Terry model: A proposed approach for evaluating palatability and preference.

The palatability of feed for dairy cows is an important consideration but is difficult to measure, particularly when considering more than 2 feeds. We outline how a combination of multiverse analysis and Bradley-Terry modeling, 2 methodological tools that have rarely been applied in dairy science, can be adapted to address this problem. Specifically, we propose to apply multiverse analysis as a way to consider a range of thresholds for how much of a mixed grass-legume (MGL) silage had to be consumed (as a percent of the total DMI) to be designated as preferred. Each threshold gives rise to a separate dataset and a corresponding fitted Bradley-Terry model. Bradley-Terry models attribute to each feed what is commonly referred to as an "ability" in the context of sports or other competitions but can be interpreted as palatability when applied to feeds. This combined approach is a way of estimating palatabilities that appropriately reflect the degree of preference cows express through their feeding behavior. It has the advantages of being transparent and relatively easy to implement. A possible disadvantage is that this method is limited to a paired comparison approach and has difficulties with main-effects statistical inference. We demonstrate the use of this methodology on an example dataset comparing MGL silages under different ensiling conditions and exposed to oxygen for different durations.

Cardiovascular and lifestyle risk factors of mild cognitive impairment in UK veterans and non-veterans.

BACKGROUND: The link between poor cardiovascular health (CVH), lifestyle and mild cognitive impairment (MCI) has been well established in the general population. However, there is limited research exploring these associations in ageing UK veterans. AIMS: This study explored the risk of MCI and its association with nine CVH and lifestyle risk factors (including diabetes, heart disease, high cholesterol, high blood pressure, obesity, stroke, physical inactivity, the frequency of alcohol consumption and smoking) in UK veterans and non-veterans. METHODS: This prospective cohort study comprised data from the PROTECT study between 2014 and 2022. Participants comprised of UK military veterans and non-veterans aged ≥50 years at baseline. Veteran status was defined using the Military Service History Questionnaire. CVH and lifestyle risk factors were defined using a combination of self-report measures, medication history or physical measurements. MCI was defined as the presence of subjective and objective cognitive impairment. RESULTS: Based on a sample of 9378 veterans (n = 488) and non-veterans (n = 8890), the findings showed the risk of MCI significantly reduced in veterans with obesity, those who frequently consumed alcohol and were physically inactive compared to non-veterans. The risk of MCI significantly increased in veterans with diabetes (hazards ratio [HR] = 2.22, 95% confidence interval [CI] 1.04-4.75, P ≤ 0.05) or high cholesterol (HR = 3.11, 95% CI 1.64-5.87, P ≤ 0.05) compared to veterans without. CONCLUSIONS: This study identified CVH and lifestyle factors of MCI in UK veterans and non-veterans. Further work is needed to understand these associations and the underpinning mechanisms which could determine intervention strategies to reduce the risk of MCI.

CTAD Task Force Paper: Neuropsychiatric Symptoms in AD: Clinical Trials Targeting Mild Behavioral Impairment: A Report from the International CTAD Task Force.

The International CTAD Task Force (TF) addressed challenges related to designing clinical trials for agitation in dementia, presenting accomplishments from the two previous TFs on neuropsychiatric symptoms (NPS). In addition, this TF proposed a paradigm shift in NPS assessment and management, presenting Mild Behavioral Impairment (MBI) as a clinical syndrome. MBI is marked by later-life emergent and persistent NPS in dementia-free older persons (ranging from cognitively unimpaired to subjective cognitive decline to mild cognitive impairment), which facilitates earlier detection and better prognostication of Alzheimer's disease (AD). The TF has made the following recommendations for incorporation of NPS into AD preventative trials: (1) clinical trials targeting improvement in MBI symptoms should be undertaken; (2) treatment trials for MBI should be disease specific and confirm the diagnosis of participants using biomarkers; trials should include measures sensitive to cognitive changes in preclinical AD, which can serve as outcome measures, in addition to changes in biomarker levels; (3) as a first step, pharmacotherapeutic trials should address the full MBI complex as well as the specific symptoms/domains that constitute MBI; (4) clinical trials using problem-adaptation psychotherapy to target affective MBI should be considered; and (5) MBI should be considered in AD trials of disease modifying therapies. The well-validated and widely-used MBI Checklist (MBI-C) is an appropriate symptom rating scale for these studies, as it was developed specifically to identify and measure MBI in dementia-free persons. Other scales such as the Neuropsychiatric Inventory (NPI) may be used, although administration at two timepoints may be necessary to operationalize the MBI criterion of symptom persistence.

Rumination moderates the longitudinal associations of awareness of age-related change with depressive and anxiety symptoms.

OBJECTIVE: Lower awareness of age-related gains (AARC-gains) and higher awareness of age-related losses (AARC-losses) may be risk factors for depressive and anxiety symptoms. We explored whether: (1) Baseline AARC-gains and AARC-losses predict depressive and anxiety symptoms at one-year follow-up; (2) age and rumination moderate these associations; (3) levels of AARC-gains and AARC-losses differ among individuals with different combinations of current and past depression and/or with different combinations of current and past anxiety. METHODS: In this one-year longitudinal cohort study participants (N = 3386; mean age = 66.0; SD = 6.93) completed measures of AARC-gains, AARC-losses, rumination, depression, anxiety, and lifetime diagnosis of depression and anxiety in 2019 and 2020. Regression models with tests of interaction were used. RESULTS: Higher AARC-losses, but not lower AARC-gains, predicted more depressive and anxiety symptoms. Age did not moderate these associations. Associations of lower AARC-gains and higher AARC-losses with more depressive symptoms and of higher AARC-losses with more anxiety symptoms were stronger in those with higher rumination. Individuals with both current and past depression reported highest AARC-losses and lowest AARC-gains. Those with current, but not past anxiety, reported highest AARC-losses. CONCLUSION: Perceiving many age-related losses may place individuals at risk of depressive and anxiety symptoms, especially those who frequently ruminate.

Using Digital Tools to Advance Alzheimer's Drug Trials During a Pandemic: The EU/US CTAD Task Force.

The 2020 COVID-19 pandemic has disrupted Alzheimer's disease (AD) clinical studies worldwide. Digital technologies may help minimize disruptions by enabling remote assessment of subtle cognitive and functional changes over the course of the disease. The EU/US Clinical Trials in Alzheimer's Disease (CTAD) Task Force met virtually in November 2020 to explore the opportunities and challenges associated with the use of digital technologies in AD clinical research. While recognizing the potential of digital tools to accelerate clinical trials, improve the engagement of diverse populations, capture clinically meaningful data, and lower costs, questions remain regarding the stability, validity, generalizability, and reproducibility of digital data. Substantial concerns also exist regarding regulatory acceptance and privacy. Nonetheless, the Task Force supported further exploration of digital technologies through collaboration and data sharing, noting the need for standardization of digital readouts. They also concluded that while it may be premature to employ remote assessments for trials of novel experimental medications, remote studies of non-invasive, multi-domain approaches may be feasible at this time.

Polygenic Risk Scoring is an Effective Approach to Predict Those Individuals Most Likely to Decline Cognitively Due to Alzheimer's Disease.

BACKGROUND: There is a clear need for simple and effective tests to identify individuals who are most likely to develop Alzheimer's Disease (AD) both for the purposes of clinical trial recruitment but also for improved management of patients who may be experiencing early pre-clinical symptoms or who have clinical concerns. OBJECTIVES: To predict individuals at greatest risk of progression of cognitive impairment due to Alzheimer's Disease in individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) using a polygenic risk scoring algorithm. To compare the performance of a PRS algorithm in predicting cognitive decline against that of using the pTau/Aß1-42 ratio CSF biomarker profile. DESIGN: A longitudinal analysis of data from the Alzheimer's Disease Neuroimaging Initiative study conducted across over 50 sites in the US and Canada. SETTING: Multi-center genetics study. PARTICPANTS: 515 subjects who upon entry to the study were diagnosed as cognitively normal or with mild cognitive impairment. MEASUREMENTS: Use of genotyping and/or whole genome sequencing data to calculate polygenic risk scores and assess ability to predict subsequent cognitive decline as measured by CDR-SB and ADAS-Cog13 over 4 years. RESULTS: The overall performance for predicting those individuals who would decline by at least 15 ADAS-Cog13 points from a baseline mild cognitive impairment in 4 years was 72.8% (CI:67.9-77.7) AUC increasing to 79.1% (CI: 75.6-82.6) when also including cognitively normal participants. Assessing mild cognitive impaired subjects only and using a threshold of greater than 0.6, the high genetic risk participant group declined, on average, by 1.4 points (CDR-SB) more than the low risk group over 4 years. The performance of the PRS algorithm tested was similar to that of the pTau/Aß1-42 ratio CSF biomarker profile in predicting cognitive decline. CONCLUSION: Calculating polygenic risk scores offers a simple and effective way, using DNA extracted from a simple mouth swab, to select mild cognitively impaired patients who are most likely to decline cognitively over the next four years.

Influence of fiber degradability of corn silage in diets with lower and higher fiber content on lactational performance, nutrient digestibility, and ruminal characteristics in lactating Holstein cows.

The effect of neutral detergent fiber (NDF) degradability of corn silage in diets containing lower and higher NDF concentrations on lactational performance, nutrient digestibility, and ruminal characteristics in lactating Holstein cows was measured. Eight ruminally cannulated Holstein cows averaging 91 ± 4 (standard error) days in milk were used in a replicated 4 × 4 Latin square design with 21-d periods (7-d collection periods). Dietary treatments were formulated to contain either conventional (CON; 48.6% 24-h NDF degradability; NDFD) or brown midrib-3 (BM3; 61.1% 24-h NDFD) corn silage and either lower NDF (LNDF) or higher NDF (HNDF) concentration (32.0 and 35.8% of ration dry matter, DM) by adjusting the dietary forage content (52 and 67% forage, DM basis). The dietary treatments were (1) CON-LNDF, (2) CON-HNDF, (3) BM3-LNDF, and (4) BM3-HNDF. Data were analyzed as a factorial arrangement of diets within a replicated Latin square design with the MIXED procedure of SAS (SAS Institute Inc., Cary, NC) with fixed effects of NDFD, NDF, NDFD × NDF, period(square), and square. Cow within square was the random effect. Time and its interactions with NDFD and NDF were included in the model when appropriate. An interaction between NDFD and NDF content resulted in the HNDF diet decreasing dry matter intake (DMI) with CON corn silage but not with BM3 silage. Cows fed the BM3 corn silage had higher DMI than cows fed the CON corn silage, whereas cows fed the HNDF diet consumed less DM than cows fed the LNDF diet. Cows fed the BM3 diets had greater energy-corrected milk yield, higher milk true protein content, and lower milk urea nitrogen concentration than cows fed CON diets. Additionally, cows fed the BM3 diets had greater total-tract digestibility of organic matter and NDF than cows fed the CON diets. Compared with CON diets, the BMR diets accelerated ruminal NDF turnover. When incorporated into higher NDF diets, corn silage with greater in vitro 24-h NDFD and lower undegradable NDF at 240 h of in vitro fermentation (uNDF240) allowed for greater DMI intake than CON. In contrast, for lower NDF diets, NDFD of corn silage did not affect DMI, which suggests that a threshold level of inclusion of higher NDFD corn silage is necessary to observe enhanced lactational performance. Results suggest that there is a maximum gut fill of dietary uNDF240 and that higher NDFD corn silage can be fed at greater dietary concentrations.

Evaluation of source of corn silage and trace minerals on rumen characteristics and passage rate of Holstein cows.

The effects of source of corn silage and trace mineral on rumen fermentation, turnover, and particle passage rates were evaluated with 8 ruminally cannulated Holstein cows averaging 83 (standard error = 5) days in milk in a replicated 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments and 28-d periods. The diets consisted (dry basis) of 55% conventional (CON) or brown midrib-3 (BM3) corn silage, 2% chopped wheat straw, and 43% grain mix with either sulfate (STM) or hydroxy (HTM) source of Cu, Zn, and Mn trace minerals. The targeted supplemental amount of Cu, Zn, and Mn was 194, 1,657, and 687 mg/d, respectively. The dietary treatments were (1) CON-STM, (2) CON-HTM, (3) BM3-STM, and (4) BM3-HTM. Dietary nutrient composition of BM3 diets averaged 32.1% amylase neutral detergent fiber on an organic matter basis (aNDFom) and 6.9% undigested neutral detergent fiber at 240 h of in vitro fermentation (uNDF240om; % of dry matter), and CON diets averaged 36.2% aNDFom and 8.6% uNDF240om (% of dry matter). Data were summarized by period and analyzed as a replicated Latin square design with fixed model effects for corn silage, trace mineral, corn silage and trace mineral interaction, period within replicated square, and replicated square using the MIXED procedure of SAS (version 9.4, SAS Institute Inc., Cary, NC). Cow within replicate was a random effect. Daily mean, standard deviation, minimum, and maximum for rumen pH were unaffected by corn silage or trace mineral source. Cows fed the CON diets had greater rumen acetate percentage than cows fed the BM3 diets (65.7 vs. 64.7 molar %). In contrast, cows fed the BM3 diets had greater rumen propionate percentage than cows fed the CON diets (21.4 vs. 20.4 molar %). Total volatile fatty acid concentration was lower for cows fed STM versus HTM in BM3 diets, but not for the cows fed the CON diets. Cows fed the BM3 diets had faster turnover rate and shorter turnover time for uNDF240om than cows fed the CON diets (3.12 vs. 2.86%/h and 33.3 vs. 36.5 h, respectively). Cows fed the BM3 diets had a faster passage rate of small and medium corn silage neutral detergent fiber particles than cows fed the CON diets (5.73 vs. 5.37%/h and 4.74 vs. 4.31%/h, respectively). We observed a corn silage by source of trace mineral interaction on organic matter and uNDF240om rumen pool size and organic matter turnover. Overall, source of corn silage had a pronounced influence on rumen dynamics presumably related to greater in vitro neutral detergent fiber digestibility and lower uNDF240om content of BM3 corn silage that allowed for faster turnover of indigestible neutral detergent fiber and greater passage rate of corn silage particles. In contrast, the source of trace mineral had much less significant effects on rumen fermentation, turnover, and particle passage rates. Corn silage-based diets intended to enhance rumen fiber fermentation, turnover, and passage are more affected by source and digestibility of neutral detergent fiber than source of dietary trace minerals.

Evaluation of source of corn silage and trace minerals on lactational performance and total-tract nutrient digestibility in Holstein cows.

We evaluated the effects of source of corn silage and trace minerals on lactational performance and total-tract digestibility (TTD) of nutrients in 16 Holstein cows averaging 82 (standard error = 3) days in milk in a replicated 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments with 28-d periods. The diets consisted [dry matter (DM) basis] of 55% conventional (CON) or brown midrib-3 (BM3) corn silage, 2% chopped wheat straw, and 43% grain mix with either sulfate (STM) or hydroxy (HTM) sources of copper, manganese, and zinc trace minerals. The targeted supplemental concentrations of copper, zinc, and manganese were 194, 1,657, and 687 mg/d, respectively. The dietary treatments were CON-STM, CON-HTM, BM3-STM, and BM3-HTM. The dietary nutrient composition of the BM3 diets averaged 32.1% amylase neutral detergent fiber on an organic matter basis (aNDFom) and 6.9% undigested neutral detergent fiber at 240 h (uNDF240om; % of DM), and CON diets averaged 36.2% aNDFom and 8.6% uNDF240om (% of DM). The average supplemental concentrations of copper, zinc, and manganese for the STM diets were 10, 41, and 64 mg/kg, respectively, and the average supplemental concentrations of copper, zinc, and manganese for the HTM diets were 10, 40, and 62 mg/kg, respectively. The average total dietary concentrations of copper, zinc, and manganese for the STM diets were 17, 104, and 60 mg/kg, respectively, and the average total dietary concentrations of copper, zinc, and manganese for the HTM diets were 17, 91, and 66 mg/kg, respectively. Data were summarized by period and analyzed as a replicated Latin square design with fixed model effects for corn silage, trace minerals, corn silage × trace mineral interaction, period within replicated square, and replicated square using the MIXED procedure of SAS. Cow within replicated square was a random effect. Cows fed the BM3 diets had greater dry matter intake (DMI) and milk yield (28.1 and 47.0 kg/d) than cows fed the CON diets (27.5 and 44.7 kg/d). We found no significant interaction between corn silage and trace minerals for DMI and milk yield. Cows fed the HTM diets (28.1 kg/d) had a greater DMI than cows fed the STM diets (27.5 kg/d). Cows fed the BM3 diets had greater TTD of DM and OM (72.8 and 74.1% of DM) than cows fed the CON diets (71.1 and 72.3% of DM). Cows fed the HTM diets had a tendency for greater TTD of aNDFom than cows fed the STM diets (56.8 vs. 54.9% of DM). Cows fed the CON diets ruminated longer during the day than cows fed the BM3 diets (524 vs. 496 min/d). Corn silage with greater NDF digestibility and lower uNDF240om enhanced DMI, milk yield, and TTD of DM and OM, and hydroxy trace minerals improved DMI and tended to improve TTD of aNDFom. The source of corn silage and trace minerals should be taken into consideration when formulating diets for high-producing dairy cows.

Influence of a novel bm3 corn silage hybrid with floury kernel genetics on lactational performance and feed efficiency of Holstein cows.

Dry matter intake, lactation performance, and chewing behavior of multiparous Holstein cows (n = 15) fed diets containing a novel bm3 corn silage hybrid with floury kernel genetics were compared with cows fed diets containing commercially available conventional and bm3 hybrids using a replicated 3 × 3 Latin square design with 28-d periods. Cows were housed in tiestalls, milked 3 times/d, and fed a total mixed ration containing 49.0% (dry matter basis) of (1) a conventional corn silage hybrid (CONV); (2) a brown midrib bm3 hybrid (BMR); or (3) a bm3 hybrid with floury kernel genetics (BMRFL). All diets contained 6.3% hay crop silage and 44.7% concentrate. Dietary nutrient composition averaged 32.7% neutral detergent fiber (NDF) and 26.3 starch (% of dry matter). Data were analyzed by ANOVA using the MIXED procedure in SAS (SAS Institute Inc., Cary, NC). The dry matter intake was greater for cows fed BMR (28.0 kg/d) compared with CONV (26.8 kg/d), whereas dry matter intake for cows fed BMRFL was intermediate (27.6 kg/d). Energy-corrected milk (ECM) yield was greater for cows fed BMR (50.3 kg/d) and BMRFL (51.8 kg/d) compared with CONV (47.2 kg/d). Milk fat yield was higher for cows fed BMRFL (1.87 kg/d) compared with CONV (1.74 kg/d) and BMR (1.80 kg/d). Milk protein yield was greater for cows fed BMR (1.49 kg/d) and BMRFL (1.54 kg/d) compared with CONV (1.36 kg/d). Milk urea-N was reduced for cows fed BMR (11.61 mg/dL) and BMRFL (11.16 mg/dL) compared with CONV (13.60 mg/dL). Feed efficiency (ECM/dry matter intake) was higher for cows fed BMRFL (1.87) compared with CONV (1.76) and BMR (1.79). Milk N efficiency was greatest for cows fed BMRFL (40.4%) followed by BMR (38.1%) and finally CONV (35.3%). Cows fed CONV chewed 5 min more per kilograms of NDF consumed than cows fed either of the BMR hybrids. No differences were observed among diets in apparent total-tract digestibility of NDF (58.1%) or starch (99.3%). Overall lactational performance was enhanced for cows fed diets containing both BMR and BMRFL hybrids versus CONV. In addition, feeding the BMRFL corn silage improved efficiency of component-corrected milk production and milk N efficiency compared with the CONV and BMR silages.

Age-related neurochemical and behavioural changes in D409V/WT GBA1 mouse: Relevance to lewy body dementia.

Heterozygous mutations in GBA1, the gene which encodes the lysosomal enzyme glucocerebrosidase (GCase), are a strong genetic risk factor for the development of Lewy body dementia (LBD). Until this point however, recapitulation of the symptoms and pathology of LBD has been limited to a homozygous GBA1 mouse model which genetically and enzymatically reflects the lysosomal storage disorder Gaucher's disease. This study reports for the first time cognitive impairment by two independent behavioural tests in heterozygous GBA1 mutant mice (D409V/WT) which demonstrate significant cognitive impairment by the age of 12 months. Furthermore, reductions in GBA1 GCase enzyme activity within the brain reflects levels seen in sporadic and GBA1 mutant LBD patients. While there is no overt deposition of Lewy bodies within the hippocampus, alterations to cholinergic machinery and glial proliferation are evident, both pathological features of LBD. Interestingly, we also describe the novel finding of significantly reduced GBA2 GCase enzyme activity specifically within the hippocampus. This suggests that reduced GBA1 GCase enzyme activity dis-equilibrates the finely balanced glycosphingolipid metabolism pathway and that reductions in GBA2 GCase enzyme could contribute to the pathological and behavioural effects seen. Overall, this study presents evidence to suggest that pathological hallmarks associated with LBD specifically affecting brain regions intrinsically linked with cognition are present in the D409V/WT mice. In the absence of Lewy body deposition, the D409V/WT mice could be considered an early pre-clinical model of LBD with potential for drug discovery. Since few robust pre-clinical models of LBD currently exist, with further characterization, the mouse model described here may contribute significantly to developments in the LBD field.

Evaluation of powdered 0.5% chlorhexidine acetate-based postmilking teat dip compared with a foamed 1% iodine-based postmilking teat dip under cold weather conditions in northern New York.

The objective of this trial was to compare a powdered 0.5% chlorhexidine acetate-based postmilking teat dip with a foamed 1% iodine-based postmilk teat dip during winter on clinical mastitis, subclinical mastitis (somatic cell count ≥200,000 cells/mL), linear score, teat skin condition, teat end score for hyperkeratosis, and risk of developing a new intramammary infection (IMI). Holstein cows (n = 331) housed in freestall and tiestall barns on one farm were blocked by pen, parity, lactation stage, and lactation performance. They were assigned randomly to a powdered chlorhexidine postmilking teat dip (PD; Derma Soft n' Dry, IBA Inc., Millbury, MA) or a foamed iodine-based postmilking teat dip (ID; FS-103, IBA Inc.). Treatments were applied for 6 wk starting January 4, 2016, for 3 milkings per day. Milk samples were collected from each quarter at the beginning and end of the trial and analyzed for aerobic culture and somatic cell count. Cows that had a clinical mastitis event during the trial were quarter sampled for aerobic culture at the time of clinical event. Teat skin condition and teat end score for hyperkeratosis were evaluated at the beginning, middle, and end of the trial based on a 3- and 5-point scale, respectively. No treatment difference was observed for linear score or teat skin condition. Teat end score was greater for ID cows compared with PD cows (2.72 vs. 2.77) at the conclusion of the trial. At the beginning of trial 102 PD quarters and 129 ID quarters had an IMI identified on aerobic culture, 402 PD and 457 ID quarters cultured negative, and 109 PD and 125 ID samples were classified as "no significant growth." At the conclusion of the trial, 129 PD and 101 ID quarters had an IMI. Use of PD resulted in a greater risk for developing a new IMI, based on bacteriological culture, at the conclusion of the trial as compared with ID (relative risk = 1.51; confidence interval: 1.10-2.07). Additionally, use of PD resulted in a greater risk as compared with ID of coagulase-negative staphylococci (relative risk = 1.5; confidence interval: 1.10-2.25) and Staphylococccus aureus (relative risk = 2.30; confidence interval: 1.04-5.07) to be present at the conclusion of the trial. In conclusion, use of PD led to a lower teat end score, an increase in new IMI, and an increased risk of coagulase-negative staphylococci and Staph. aureus compared with ID after 6 wk of product use.

Pimavanserin in Alzheimer's Disease Psychosis: Efficacy in Patients with More Pronounced Psychotic Symptoms.

BACKGROUND: Pimavanserin is a 5-HT2A receptor inverse agonist/antagonist and is approved in the United States for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. OBJECTIVE: Evaluate the efficacy of pimavanserin on symptoms of psychosis in patients with Alzheimer's disease (AD). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Nursing home residents. PARTICIPANTS: Patients with AD psychosis. INTERVENTIONS: Pimavanserin 34 mg or placebo daily for 12 weeks. MEASUREMENTS: The primary endpoint was mean change from baseline at Week 6 on the Neuropsychiatric Inventory-Nursing Home Version psychosis score (NPI-NH-PS). In the prespecified subgroup analysis, the mean change in NPI-NH-PS and the responder rates among those with baseline NPI-NH-PS ≥12 were evaluated. RESULTS: Of 181 patients randomized (n=90 pimavanserin; n=91 placebo), 57 had baseline NPI-NH-PS ≥12 (n=27 pimavanserin; n=30 placebo). In this severe subgroup, large treatment effects were observed (delta=-4.43, Cohen's d=-0.73, p=0.011), and ≥30% improvement was 88.9% vs. 43.3% (p<0.001) and ≥50% improvement was 77.8% vs. 43.3% (p=0.008) for pimavanserin and placebo, respectively. The rate of adverse events (AEs) in the severe subgroup was similar between treatment groups, and urinary tract infection, fall, and agitation were most frequent. Serious AEs was similar with pimavanserin (17.9%) and placebo (16.7%) with fewer discontinuations due to AEs with pimavanserin (7.1%) compared to placebo (10.0%). Minimal change from baseline occurred for the mean MMSE score over 12 weeks. CONCLUSIONS: Pimavanserin demonstrated significant efficacy in AD psychosis in patients with higher baseline severity of psychotic symptoms (NPI-NH-PS ≥12). Treatment with pimavanserin showed an acceptable tolerability profile.

Impaired chronic pain-like behaviour and altered opioidergic system in the TASTPM mouse model of Alzheimer's disease.

BACKGROUND: Chronic pain conditions, especially osteoarthritis (OA), are as common in individuals with Alzheimer's disease (AD) as in the general elderly population, which results in detrimental impact on patient's quality of life. However, alteration in perception of pain in AD coupled with deteriorating ability to communicate pain sensations often result in under-diagnosis and inappropriate management of pain. Therefore, a better understanding of mechanisms in chronic pain processing in AD is needed. Here, we explored the development and progression of OA pain and the effect of analgesics in a transgenic mouse model of AD. METHODS: Unilateral OA pain was induced chemically, via an intra-articular injection of monosodium iodoacetate (MIA) in the left knee joint of AD-mice (TASTPM) and age- and gender-matched C57BL/6J (WT). Pharmacological and biochemical assessments were conducted in plasma and spinal cord tissue. RESULTS: MIA resulted in hind paw mechanical hypersensitivity (allodynia), initiating on day 3, in TASTPM and WT controls. However, from 14 to 28 days, TASTPM displayed partial attenuation of allodynia and diminished spinal microglial response compared to WT controls. Naloxone, an opioid antagonist, re-established allodynia levels as observed in the WT group. Morphine, an opioid agonist, induced heightened analgesia in AD-mice whilst gabapentin was devoid of efficacy. TASTPM exhibited elevated plasma level of ß-endorphin post-MIA which correlated with impaired allodynia. CONCLUSIONS: These results indicate an alteration of the opioidergic system in TASTPM as possible mechanisms underlying impaired persistent pain sensitivity in AD. This work provides basis for re-evaluation of opioid analgesic use for management of pain in AD. SIGNIFICANCE: This study shows attenuated pain-like behaviour in a transgenic mouse model of Alzheimer's disease due to alterations in the opioidergic system and central plasticity mechanisms of persistent pain.

Pimavanserin: Potential Treatment For Dementia-Related Psychosis.

Psychosis is common across dementia types with a prevalence of 20% to 70%. Currently, no pharmacologic treatment is approved for dementia-related psychosis. Atypical antipsychotics are frequently used to treat these disorders, despite significant safety concerns. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved in the U.S. for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Patients in the pimavanserin group experienced a significant (p=0.001) improvement in Scale for the Assessment of Positive Symptoms - Parkinson's disease (SAPS-PD) scores vs. placebo. In a subgroup analysis of patients with cognitive impairment (MMSE score ≥21 but ≤24), the observed improvement on the SAPS-PD with pimavanserin (N=50) was also significant (p=0.002) and larger than in the overall study population without an adverse effect on cognition. In a Phase 2 study with pimavanserin in Alzheimer's disease psychosis, pimavanserin significantly (p=0.045) improved psychosis at Week 6 vs. placebo on the NPI-NH Psychosis Score (PS). In a prespecified subgroup of patients with a baseline NPI-NH PS ≥12, a substantively larger treatment effect (p=0.011) was observed vs. participants with NPI-NH PS <12. The results of these studies in cognitively impaired patients with PDP provided the scientific foundation for an ongoing study of pimavanserin for treating patients with dementia-related psychosis associated with the most common neurodegenerative disorders. The study uses a relapse-prevention design with the endpoint of time-to-relapse of psychosis to evaluate the long-term efficacy and safety of pimavanserin as a potential treatment for hallucinations and delusions of dementia-related psychosis.

Online assessment of risk factors for dementia and cognitive function in healthy adults.

OBJECTIVE: Several potentially modifiable risk factors for cognitive decline and dementia have been identified, including low educational attainment, smoking, diabetes, physical inactivity, hypertension, midlife obesity, depression, and perceived social isolation. Managing these risk factors in late midlife and older age may help reduce the risk of dementia; however, it is unclear whether these factors also relate to cognitive performance in older individuals without dementia. METHOD: Data from 14 201 non-demented individuals aged >50 years who enrolled in the online PROTECT study were used to examine the relationship between cognitive function and known modifiable risk factors for dementia. Multivariate regression analyses were conducted on 4 cognitive outcomes assessing verbal and spatial working memory, visual episodic memory, and verbal reasoning. RESULTS: Increasing age was associated with reduced performance across all tasks. Higher educational achievement, the presence of a close confiding relationship, and moderate alcohol intake were associated with benefits across all 4 cognitive tasks, and exercise was associated with better performance on verbal reasoning and verbal working memory tasks. A diagnosis of depression was negatively associated with performance on visual episodic memory and working memory tasks, whereas being underweight negatively affected performance on all tasks apart from verbal working memory. A history of stroke was negatively associated with verbal reasoning and working memory performance. CONCLUSION: Known modifiable risk factors for dementia are associated with cognitive performance in non-demented individuals in late midlife and older age. This provides further support for public health interventions that seek to manage these risk factors across the lifespan.

Antidepressants and mortality risk in a dementia cohort: data from SveDem, the Swedish Dementia Registry.

BACKGROUND: The association between mortality risk and use of antidepressants in people with dementia is unknown. OBJECTIVE: To describe the use of antidepressants in people with different dementia diagnoses and to explore mortality risk associated with use of antidepressants 3 years before a dementia diagnosis. METHODS: Study population included 20 050 memory clinic patients from the Swedish Dementia Registry (SveDem) diagnosed with incident dementia. Data on antidepressants dispensed at the time of dementia diagnosis and during 3-year period before dementia diagnosis were obtained from the Swedish Prescribed Drug Register. Cox regression models were used. RESULTS: During a median follow-up of 2 years from dementia diagnosis, 25.8% of dementia patients died. A quarter (25.0%) of patients were on antidepressants at the time of dementia diagnosis, while 21.6% used antidepressants at some point during a 3-year period before a dementia diagnosis. Use of antidepressant treatment for 3 consecutive years before a dementia diagnosis was associated with a lower mortality risk for all dementia disorders and in Alzheimer's disease. CONCLUSION: Antidepressant treatment is common among patients with dementia. Use of antidepressants during prodromal stages may reduce mortality in dementia and specifically in Alzheimer's disease.

Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice.

PPARδ (peroxisome proliferator-activated receptor δ) mediates inflammation in response to lipid accumulation. Systemic administration of a PPARδ agonist can ameliorate atherosclerosis. Paradoxically, genetic deletion of PPARδ in hematopoietic cells led to a reduction of atherosclerosis in murine models, suggesting that downregulation of PPARδ expression in these cells may mitigate atherogenesis. To advance this finding forward to potential clinical translation through hematopoietic stem cell transplantation-based gene therapy, we employed a microRNA (miRNA) approach to knock down PPARδ expression in bone marrow cells followed by transplantation of the cells into LDLR-/- mice. We found that knockdown of PPARδ expression in the hematopoietic system caused a dramatic reduction in aortic atherosclerotic lesions. In macrophages, a key component in atherogenesis, knockdown of PPARδ led to decreased expression of multiple pro-inflammatory factors, including monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1ß and IL-6. Expression of CCR2, a receptor for MCP-1, was also decreased. The downregulation of pro-inflammatory factors is consistent with significant reduction of macrophage presence in the lesions, which may also be attributable to elevation of ABCA1 (ATP-binding cassette, subfamily A, member 1) and depression of adipocyte differentiate-related protein. Furthermore, the abundance of both MCP-1 and matrix metalloproteinase-9 proteins was reduced in plaque areas. Our results demonstrate that miRNA-mediated PPARδ knockdown in hematopoietic cells is able to ameliorate atherosclerosis.

Short communication: Effect of on-farm feeding practices on rumen protected lysine products.

Two independent studies were conducted to determine whether mechanical mixing of total mixed ration (TMR) or TMR dry matter alters Lys release from 6 rumen-protected Lys (RPL) products (A, B, C, D, E, and F). In the first study, routine mixing procedures were simulated to determine if inclusion of RPL products in TMR altered in situ release of Lys. Following mixing, Dacron bags containing RPL products were ruminally incubated for 0, 6, 12, or 24 h to determine Lys release. The second study occurred independently of the first, in which Lys release from RPL products was evaluated when incorporated into a TMR that differed in dry matter (DM) content. Bags containing TMR and RPL product mixture were stored at room temperature for 0, 6, 18, and 24 h to simulate RPL product exposure to TMR when mixed and delivered once per day. Concentration of free Lys in both studies was determined using ultra-performance liquid chromatography. Following mechanical mixing, ruminal Lys release was significantly greater for C and tended to increase for F. Mechanical mixing did not alter ruminal Lys release from other RPL products evaluated. Hours of ruminal incubation significantly altered Lys release for all products evaluated, and a significant interaction of mechanical mixing and hours of ruminal incubation was observed for A and C. Exposure to lower TMR DM (40.5 versus 51.8%) significantly increased Lys release from B but did not alter Lys release from the other RPL products evaluated. Moreover, time of exposure to TMR significantly increased Lys release from all RPL products evaluated, and a significant interaction of TMR DM and time of exposure to TMR was observed for B and E. These data suggest mechanical mixing and variation in TMR DM may compromise the rumen protection of RPL products; therefore, on-farm feeding practices may alter efficacy of RPL products in dairy rations.