Tamsulosin and the risk of dementia in older men with benign prostatic hyperplasia

 
Comparative Study

 

2018 Mar;27(3):340-348.

 doi: 10.1002/pds.4361. Epub 2018 Jan 9.

Tamsulosin and the risk of dementia in older men with benign prostatic hyperplasia

 
Affiliations 

Abstract

Purpose: Clinicians use tamsulosin, an α1-adrenoceptor antagonist, to manage symptomatic benign prostatic hyperplasia (BPH). Because α1-adrenoceptors are also present in the brain, the potential exists for adverse effects on cognitive functions. We explored the association between tamsulosin use and dementia risk.

Methods: We used Medicare data (2006-2012) to conduct a cohort study among patients aged ≥65 years and diagnosed with BPH. Men taking tamsulosin (n = 253 136) were matched at a 1:1 ratio using propensity-scores to each of 6 comparison cohorts: patients who used no BPH-medication (n = 180 926), and patients who used the following alternative-BPH-medications: doxazosin (n = 28 581), terazosin (n = 23 858), alfuzosin (n = 17 934), dutasteride (n = 34 027), and finasteride (n = 38 767). Assessment began following the first fill of BPH-medication to identify incident dementia by ICD-9 diagnosis codes. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for dementia using Cox proportional hazard regression for each of the 6 propensity-score-matched cohort-pairs.

Results: The median follow-up period for all cohorts was 19.8 months. After propensity-score matching, the tamsulosin cohort had an incidence of dementia of 31.3/1000 person-years compared with only 25.9/1000 person-years in the no-BPH-medication cohort. The risk of dementia was significantly higher in the tamsulosin cohort, when compared with the no-BPH-medication cohort (HR [95% CI]: 1.17 [1.14, 1.21]) and each of the alternative-BPH-medication cohorts: doxazosin (1.20 [1.12, 1.28]), terazosin (1.11 [1.04, 1.19]), alfuzosin (1.12 [1.03, 1.22]), dutasteride (1.26 [1.19, 1.34]), and finasteride (1.13 [1.07, 1.19]). The significance of these findings persisted in sensitivity analyses.

Conclusion: Tamsulosin may increase the risk of dementia in older men with BPH.

Keywords: benign prostatic hyperplasia; claims database; dementia; pharmacoepidemiology; propensity score matching; retrospective cohort study; tamsulosin.

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LED strobe lights clear Alzheimer plaques?

Integrative neuroscience…. A rare species indeed.

Very interesting and well written article on potential new treatments:

https://www.quantamagazine.org/stimulated-brain-waves-offer-a-possible-treatment-for-alzheimers-20200527/

 

 

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‘On-Demand’ Fast Mobilizes Fat; Low-Carb Breakfast Stymies Hunger – Medscape – Oct 12, 2020.

‘On-Demand’ Fast Mobilizes Fat; Low-Carb Breakfast Stymies Hunger – Medscape – Oct 12, 2020.

 

‘On-Demand’ Fast Mobilizes Fat; Low-Carb Breakfast Stymies Hunger

Becky McCall

October 12, 2020

Greater fat tissue mobilization can be achieved through early-day fasting in comparison to consuming a low-carbohydrate breakfast or a Mediterranean-style breakfast, shows a small study that explored the short-term effects of intermittent fasting by lean people.

 

The study also found that consumption of a low-carbohydrate breakfast results in longer suppression of hunger compared to a Mediterranean breakfast.

Dimitrios Tsilingiris, MD, PhD, led the study and presented the findings recently at the virtual meeting of the European Association for the Study of Diabetes (EASD).

“Through fasting intervals as short as those achievable through a 16:8 restricted feeding scheme, a substantially and measurably increased fat tissue mobilization ― as indexed by increased ketone body production ― may occur,” said Tsilingiris, reporting the main finding.

He added that for most ketogenic diets, time is needed for the switch toward fat burning, but the findings from this study could provide support for an “on-demand” application of this strategy.

“The quite high subjective hunger scores at the end of the fasting sessions should also be taken into account, since the feeling of hunger may obviously drive the subsequent caloric quantity intake,” Tsilingiris, formerly of Laiko General Hospital, Athens, Greece, but now based at the University Hospital Heidelberg, in Germany, pointed out.

Anne-Marie Aas, PhD, clinical dietitian and associate professor at Oslo University Hospital, Oslo, Norway, was session moderator. She told Medscape Medical News that she welcomed the study because there is a lack of human studies of the clinical implications of different forms of intermittent fasting.

“The findings from this Greek study in healthy people is interesting but not surprising, since a prolonged fast would naturally prolong the time the metabolism yields energy from fat stores,” she said.

“The most interesting finding is perhaps that fasting resulted in increased hunger, while the low-carb breakfast suppressed appetite for longer than the typical Mediterranean breakfast.” she said.

 

“This is in line with an earlier study from the same group [as reported from EASD 2018] showing that morning-time carbohydrate restriction resulted in greater weight loss in obese individuals over a 2-month period,” she noted.

 

First Study of Short-Term “On-Demand” Intermittent Fasting

Tsilingiris explained that evidence in the literature suggests that intermittent fasting is associated with numerous health benefits. The term refers to a relatively heterogeneous group of dietary habits that commonly include prolonged fasting intervals within a month (periodic fasting), a week (5:2, alternate day fasting), or a day (time-restricted feeding, 16:8).

 

In theory, intermittent fasting leads to loss of fat tissue through a metabolic milieu that promotes fat mobilization, he said.

 

“To our knowledge,” he said, “this hypothesis regarding the shortest-term application of intermittent fasting ― that is, the increasingly popular 16:8 ― has not been put to the test until now.”

 

He and his team investigated early-day fasting for adipose tissue mobilization, as indicated by β-hydroxybutyrate levels, and they compared this approach with two different kinds of breakfast.

 

“We compared the ketogenic response of [early-day] fasting to that following a zero-carb and a standard Mediterranean breakfast,” Tsilingiris said.

 

The crossover study included 10 normal-weight (body mass index [ΒΜI] < 25 kg/m2) healthy individuals.

 

In the study, participants had dinner at 8:00 PM. The following morning, they either had breakfast or they fasted from 8:00 AM to 2:00 PM.

 

Breakfasts consisted of either a Mediterranean breakfast (500 kcal of 50% carbohydrate, 30% fat, 20% protein) or a zero-carbohydrate breakfast (500 kcal, 60% fat, 40% protein).

 

The sessions were held at least 1 week apart but no more than 3 weeks apart. All participants had identical dinners on the preceding evening.

 

Early Day Fasting Shows Highest Fat Mobilization

Insulin levels were lower and mobilization of fat tissue was greater (highest beta-hydroxybutyrate levels) when the participants were fasting intermittently in comparison to when they were having breakfast (either zero-carbohydrate or Mediterranean style).

 

When fasting, the adjusted area under the curve representing β-hydroxybutyrate concentration was 6.17 mmolh/L. By contrast, it was 4.16 mmolh/L after the zero-carbohydrate breakfast and 3.65 mmolh/L after the Mediterranean breakfast, when adjusted for fasting duration HOMA-R and triglyceride/HDL ratio.

 

Factors found to be associated with fat mobilization were fasting duration (P = .040), BMI (= .020), and insulin resistance (HOMA-R; P = .059).

 

For the individuals who had breakfast, there were no differences in ketone body levels and beta-hydroxybutyrate levels, regardless of the type of breakfast they had.

 

Low-Carb Breakfast Staved Off Hunger for Longer

However, there was a difference in hunger score regarding the two breakfasts.

 

“The fasting state was associated with high subjective hunger scores, while a more durable hunger suppression was achieved after the low-carb breakfast intake compared to the Mediterranean breakfast,” reported Tsilingiris.

 

In the late postprandial stage (3 – 6 hours after eating), measures of hunger on the visual analogue scale were 16.0, 7.5, and 12.0 for fasting, zero-carbohydrate breakfast, and Mediterranean breakfast, respectively.

 

There was a small but significant difference in insulin levels across all three groups.

 

Insulin levels were “quite a lot higher in the Mediterranean compared to the low-carbohydrate breakfast, but that did not translate to a measurable difference in ketone body production between the two approaches,” Tsilingiris explained.

 

He speculated on why this might be the case: “It doesn’t take a whole lot of insulin to inhibit ketogenesis and/or lipolysis among lean, apparently metabolic healthy individuals.”

 

There are undoubtedly “many other regulators ― for example, hormonal, rather than just insulin, that play a role in the modulation of the studied effects ― that we did not take into account in the current study and could have influenced these observations,” he noted.

 

In a comment, Aas pointed out, “Another study presented at another EASD session [Krista Varady, University of Illinois: Clinical Application of Intermittent Fasting] showed that similar interventions over 3 months resulted in an unintentional decrease in calorie intake of approximately 500 kcal/d, weight reduction, and improvements in several metabolic risk factors.”

 

Tsilingiris and Aas have disclosed no relevant financial relationships.

 

European Association for the Study of Diabetes (EASD) 2020 Annual Meeting: Presented September 24, 2020.

 

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Does the ε2 allele remain protective against β-amyloid (Aβ) accumulation in the presence of the ε4 allele?

Does the ε2 allele remain protective against β-amyloid (Aβ) accumulation in the presence of the ε4 allele? Yes, but so does good sleep, low HbA1c, low anxiety, low inflammation etc.

Association Between Apolipoprotein E ε2 vs ε4, Age, and β-Amyloid in Adults Without Cognitive Impairment

JAMA Neurol. Published online October 12, 2020. doi:10.1001/jamaneurol.2020.3780
 
Key Points

Question  Does the ε2 allele remain protective against β-amyloid (Aβ) accumulation in the presence of the ε4 allele?

Findings  In this cross-sectional study of 4432 older participants without cognitive impairment, apolipoprotein E ε2 (APOE ε2) was associated with a reduction in both the overall and age-dependent level of Aβ in the presence of ε4, with Aβ levels in the APOE ε24 group (n = 115) increasing at significantly less than half the rate with respect to increasing age compared with the APOE ε34 group (n = 1295).

Meaning  The protective outcome of carrying an ε2 allele in the presence of an ε4 allele against Aβ accumulation may inform future development of disease-modifying Alzheimer disease therapies.

Abstract

Importance  Although the most common recent approach in Alzheimer disease drug discovery is to directly target the β-amyloid (Aβ) pathway, the high prevalence of apolipoprotein E ε4 (APOE ε4) in Alzheimer disease and the ease of identifying ε4 carriers make the APOE genotype and its corresponding protein (apoE) an appealing therapeutic target to slow Aβ accumulation.

Objective  To determine whether the ε2 allele is protective against Aβ accumulation in the presence of the ε4 allele and evaluate how age and the APOE genotype are associated with emerging Aβ accumulation and cognitive dysfunction.

Design, Setting, and Participants  This cross-sectional study used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (A4 Study) collected from April 2014 to December 2017 and analyzed from November 2019 to July 2020. Of the 6943 participants who were a part of the multicenter clinical trial screening visit, 4432 were adults without cognitive impairment aged 65 to 85 years who completed a fluorine 18–labeled (18F)-florbetapir positron emission tomography scan, had APOE genotype information, and had a Clinical Dementia Rating of 0. Participants who were taking a prescription Alzheimer medication or had a current serious or unstable illness that could interfere with the study were excluded.

Main Outcomes and Measures  Aβ pathology, measured by 18F-florbetapir positron emission tomography and cognition, measured by the Preclinical Alzheimer Cognitive Composite.

Results  A total of 4432 participants were included (mean [SD] age, 71.3 [4.7] years; 2634 women [59.4%]), with a mean (SD) of 16.6 (2.8) years of education and 1512 (34.1%) with a positive Aβ level. APOE ε2 was associated with a reduction in both the overall (standardized uptake value ratio [SUVR], ε24, 1.11 [95% CI, 1.08-1.14]; ε34, 1.18 [95% CI, 1.17-1.19]) and the age-dependent level of Aβ in the presence of ε4, with Aβ levels in the APOE ε24 group (n = 115; ε24, 0.005 SUVR increase per year of age) increasing at less than half the rate with respect to increasing age compared with the APOE ε34 group (n = 1295; 0.012 SUVR increase per year of age; P = .04). The association between Aβ and decreasing Preclinical Alzheimer Cognitive Composite scores did not differ by APOEgenotype, and the reduced performance on the Preclinical Alzheimer Cognitive Composite in APOE ε4 carriers compared with noncarriers was completely mediated by Aβ (unadjusted difference in composite scores between ε4 carriers and noncarriers = –0.084, P = .005; after adjusting for 18F-florbetapir = –0.006, P = .85; after adjusting for 18F-florbetapir and cardiovascular scores = –0.009, P = .78).

Conclusions and Relevance  These findings suggest that the protective outcome of carrying an ε2 allele in the presence of an ε4 allele against Aβ accumulation is important for potential treatments that attempt to biochemically mimic the function of the ε2 allele in order to facilitate Aβ clearance in ε4 carriers. Such a treatment strategy is appealing, as ε4 carriers make up approximately two-thirds of patients with Alzheimer disease dementia. This strategy could represent an early treatment option, as many ε4 carriers begin to accumulate Aβ in early middle age.

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Metformin Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes

Metformin Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes: The Sydney Memory and Ageing Study

Katherine Samaras, Steve Makkar, John D. Crawford, Nicole A. Kochan, Wei Wen, Brian Draper, Julian N. Trollor, Henry Brodaty, Perminder S. Sachdev

Abstract

OBJECTIVE Type 2 diabetes (diabetes) is characterized by accelerated cognitive decline and higher dementia risk. Controversy exists regarding the impact of metformin, which is associated with both increased and decreased dementia rates. The objective of this study was to determine the association of metformin use with incident dementia and cognitive decline over 6 years in participants with diabetes compared with those not receiving metformin and those without diabetes.

RESEARCH DESIGN AND METHODS A prospective observational study was conducted of N= 1,037 community-dwelling older participants without dementia aged 70–90 years at baseline (the Sydney Memory and Ageing Study). Exclusion criteria were dementia, major neurological or psychiatric disease, or progressive malignancy. Neuropsychological testing measured cognitive function every 2 years; a battery of tests measured executive function, memory, attention/speed, language, and visuospatial function individually. These were used to determine the measure of global cognition. Incident dementia was ascertained by a multidisciplinary panel. Total brain, hippocampal, and parahippocampal volumes were measured by MRI at baseline and 2 years (n = 526). Data were analyzed by linear mixed modeling, including the covariates of age, sex, education, BMI, heart disease, hypertension, stroke, smoking, and apolipoprotein Eε4 carriage.

RESULTS Of n = 1,037, 123 had diabetes; 67 received metformin (DM+MF) and were demographically similar to those who did not (DM-noMF) and participants without diabetes (no-DM). DM+MF had significantly slower global cognition and executive function decline compared with DM-noMF. Incident dementia was significantly higher in DM-noMF compared with DM+MF (odds ratio 5.29 [95% CI 1.17–23.88]; P = 0.05).

CONCLUSIONS Older people with diabetes receiving metformin have slower cognitive decline and lower dementia risk. Large randomized studies in people with and without diabetes will determine whether these associations can be attributed to metformin.

Finally becoming mainstream. Why did this take so long?

https://care.diabetesjournals.org/content/early/2020/09/22/dc20-0892

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