Tag: cognitive decline

Unexpected Cognitive Effect of ARNI Therapy in Heart Failure

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Despite fears about cognitive decline in heart failure patients taking angiotensin receptor-neprilysin inhibition (ARNI), an observational study found that the drug instead had a protective effect.

Adults with systolic heart failure taking sacubitril/valsartan (Entresto) starting from 2015–2019 had fewer neurocognitive diagnoses up to 5 years later compared with a those staying on angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) alone.

  • Alzheimer’s disease: 1.11% on ARNI vs 1.24% on ACE inhibitors/ARBs
  • Dementia: 4.18% vs 6.49%
  • Cognitive decline: 11.82% vs 14.53%

On the basis of the PARAGON-HF trial,  sacubitril/valsartan won a broad heart failure indication, reaching into the normal ejection fraction range, for prevention of cardiovascular death and hospitalisation.

“Experimental studies with sacubitril/valsartan have fueled theoretical concerns about neurocognitive side effects, but long-term clinical data are scarce,” noted Prabhjot Grewal, MD, of Stony Brook University Hospital in New York, who reported the findings for the Heart Failure Society of America annual virtual meeting.

She explained that neprilysin inhibition by sacubitril could theoretically inadvertently interfere with the degradation of beta amyloid in the central nervous system, where neprilysin is expressed, in addition to the kidneys where it is most abundant.

However there are many factors in cognitive decline in heart failure, such as the circulatory deficit itself; vascular dementia resulting from comorbidities such as hypertension and vascular disease; and Alzheimer’s disease or Lewy body dementia. By ameliorating heart failure and improving blood pressure, drugs such as ACE inhibitors and sacubitril/valsartan could protect cognition, according to Mandeep Mehra, MBBS, MSc, of Brigham and Women’s Hospital and Harvard Medical School in Boston.

“Thus, even if a drug like sacubitril may cause worsening of one type of cognitive decline, it may be counterbalanced by positive effects on other domains since the reasons for cognitive decline in such patients are almost always multi-factorial and the signals may therefore be obfuscated in general analyses,” explained Mehra, who was not involved in the study.

The authors acknowledged that the observational study lacked systematic characterisation, and also leaves room for residual confounding despite propensity matching.

“This is why we require a prospective study that includes mechanistic end points (degree of beta amyloid protein deposition) in concert with functional outcomes (sensitive measures of cognitive decline) while ensuring that sufficient time is allowed to be evaluated since these are slow and subtle effects,” Mehra said, adding that the PERSPECTIVE trial will likely publish findings in 2022.

Source: MedPage Today

Small Study Hints at Omega-3 Protection of Memory in Alzheimer’s

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A first-of-its-kind study on Alzheimer’s disease found an indication that omega-3 fatty acids taken early on protect against Alzheimer’s disease, despite not finding biomarkers in patients’ cerebrospinal fluid.

The researchers published their findings in Journal of Alzheimer’s Disease.

“We are careful not to draw any wider conclusions, but we can see a difference in the results of the memory tests. Patients who were taking omega-3 supplements at an early stage of the disease scored better,” cautioned Yvonne Freund-Levi, researcher in neuroscience at Örebro University.

The small study enrolled 33 patients, 18 of which were given omega-3 supplements morning and evening, and15 were in the control group. Spinal fluid samples were collected, and patients performed a memory test at the start of the study and after six months.

“We can see that the memory function of the patients in the group that had taken omega-3 is stable, whereas the patients in the control group have deteriorated. That’s what the memory tests show,” said Yvonne Freund-Levi.

“But we can’t see any differences between the groups when we look at the various biomarkers in the spinal fluid samples.”

However there are differences within the group given omega-3: an increase of two of the markers that are linked to damaged nerve cells. There is no clinical link to the memory tests, however.

“Even if this data isn’t enough for us to change our recommendations to patients at this time, it is an interesting material for researchers to build on.”

This study is based on a larger study with over 200 patients with mild to moderate Alzheimer’s disease, initiated by Yvonne Freund-Levi and her research team 15 years ago. In that previous study, the researchers found that omega-3 transfers from the supplements to the brain.

“We are cautious about giving recommendations, but we know that starting early is by far the best thing – it is difficult to influence the disease at a later stage. The best piece of advice we have to offer at the moment is to be physically active and to include omega-3 in your diet – in the form of oily fish or as supplements.”

In future, researchers will be able to measure biomarkers in blood samples rather than having to perform spinal tap procedures.

“We have already tested this approach at Sahlgrenska University Hospital. Without a doubt, it is so much better for the patients.”

Source: Örebro University

Some Cognitive Abilities Improve With Age

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While it has long been held that all cognitive abilities decline with age, new research shows that some of these abilities can actually improve over a lifetime.

The findings, published in Nature Human Behavior, show that two key brain functions, focusing and attending to new information, can in fact improve in older individuals. These functions underlie key aspects of cognition including memory, decision making, and self-control, and even navigation, math, language and reading.

“These results are amazing, and have important consequences for how we should view aging,” said senior investigator, Michael T Ullman, PhD, a professor in the Department of Neuroscience and director of Georgetown’s Brain and Language Lab.

“People have widely assumed that attention and executive functions decline with age, despite intriguing hints from some smaller-scale studies that raised questions about these assumptions,” he said. “But the results from our large study indicate that critical elements of these abilities actually improve during aging, likely because we simply practice these skills throughout our life.”

“This is all the more important because of the rapidly aging population, both in the U.S. and around the world,” Ullman said, adding that with further research, it may be possible to deliberately improve these skills to protect against cognitive decline.

The research team explored three separate components of attention and executive function in a group of 702 participants aged 58 to 98. This age range was chosen since this is when cognition often changes the most during aging.

The components they studied are the brain networks involved in alerting, orienting and executive inhibition. Each has different characteristics and relies on different brain areas and different neurochemicals and genes. Therefore, Ullman and Veríssimo reasoned, the networks may also show different aging patterns.

Alerting is characterised by a state of enhanced vigilance and preparedness, while orienting involves shifting brain resources to a particular location in space. The executive network inhibits distracting or conflicting information, allowing us to focus on what’s important.

“We use all three processes constantly,” Veríssimo explains. “For example, when you are driving a car, alerting is your increased preparedness when you approach an intersection. Orienting occurs when you shift your attention to an unexpected movement, such as a pedestrian. And executive function allows you to inhibit distractions such as birds or billboards so you can stay focused on driving.”

Surprisingly, only alerting abilities declined with age while both orienting and executive inhibition actually improved.

The researchers hypothesis is that because orienting and inhibition are simply skills that allow selective attention, these skills can improve with lifelong practice. Ullman and Veríssimo suggest that these gains can be large enough to outweigh the underlying neural declines. Alerting declines, they believe, because this basic state of vigilance and preparedness cannot improve with practice.  
“Because of the relatively large number of participants, and because we ruled out numerous alternative explanations, the findings should be reliable and so may apply quite broadly,” Veríssimo said, adding that “because orienting and inhibitory skills underlie numerous behaviors, the results have wide-ranging implications.”

“The findings not only change our view of how aging affects the mind, but may also lead to clinical improvements, including for patients with aging disorders such as Alzheimer’s disease,” said Ullman. 

Source: Georgetown University Medical Center

A Cognitive Rejuvenating Effect with Gut Microbe Transplant

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A novel approach to reverse aspects of ageing-related deterioration in the brain and cognitive function via the microbes in the gut was revealed in research published in Nature Aging.

With ageing populations increasing worldwide, a key challenge is the development of strategies to maintain healthy brain function. This ground-breaking research with gut microbes lays open new possibilities such as microbial-based interventions to slow down brain ageing and cognitive problems associated with it.

The work was carried out by researchers at Microbiome Ireland (APC) at University College Cork (UCC).

There is a growing appreciation of the importance of the microbes in the gut on all aspects of physiology and medicine. In this most recent study, the authors demonstrated that by transplanting gastrointestinal microbes from young into old mice, they were able to rejuvenate aspects of brain and immune function.

Study leader Professor John F Cryan said: “Previous research published by the APC and other groups internationally has shown that the gut microbiome plays a key role in aging and the ageing process. This new research is a potential game changer, as we have established that the microbiome can be harnessed to reverse age-related brain deterioration. We also see evidence of improved learning ability and cognitive function”.

Despite the promising results, Prof Cryan cautioned that “it is still early days and much more work is needed to see how these findings could be translated in humans”.

APC Director Prof Paul Ross stated that “This research of Prof Cryan and colleagues further demonstrates the importance of the gut microbiome in many aspects of health, and particularly across the brain/gut axis where brain functioning can be positively influenced. The study opens up possibilities in the future to modulate gut microbiota as a therapeutic target to influence brain health”.

Source: University College Cork

Statins not Associated With Cognitive Decline

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A new study has found that statin use in adults 65 years old or older is not associated with incident dementia, mild cognitive impairment (MCI) or decline in individual cognition domains.

Major health concerns in the elderly, cognitive decline and dementia affect about 10% of people over 60 years old. Statins are used to reduce low-density lipoprotein cholesterol, and are a fundamental treatment for prevention of primary and secondary cardiovascular disease (CVD) events. 
In 2012 the Food and Drug Administration issued a warning about cases of apparent short-term cognitive impairment with statin use, while acknowledging that the cardiovascular benefits outweigh their risks. Systematic reviews have since shown insufficient evidence on the impact of statins, and research has shown mixed results, with some showing a neurocognitive benefit of statins and others reporting a null effect.

“With statins being increasingly prescribed to older adults, their potential long-term effects on cognitive decline and dementia risk have attracted growing interest,” said lead author Zhen Zhou, PhD, Menzies Institute for Medical Research at the University of Tasmania. “The present study adds to previous research by suggesting that statin use at baseline was not associated with subsequent dementia incidence and long-term cognitive decline in older adults.”

Researchers of this study analysed data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. ASPREE was a large prospective, randomized placebo-controlled trial of daily low-dose aspirin with adults 65 or older. One of the key selection criteria of ASPREE was that participants had to have a score of 78 for the Modified Mini-Mental State Examination test, a screening test for cognitive abilities, at enrollment.

The study had 18 846 participants, grouped by their baseline statin use (31.3% of participants) versus non-statin use. The study aimed to measure outcomes including incident dementia and its subclassifications (probable Alzheimer’s disease [AD], mixed presentations); MCI and its subclassifications (MCI consistent with AD, MCI-other); changes in domain-specific cognition including global cognition, memory, language and executive function, and psychomotor speed; and in the composite of these domains.

After a median of 4.7 years of follow-up, researchers found 566 incident cases of dementia (including probable AD and mixed presentations). Compared with no statin use, statin use was not associated with risk of all-cause dementia, probable AD or mixed presentations of dementia. There were 380 incident cases of MCI found (including MCI consistent with AD and MCI-other). Compared to no statin use, statin use was not associated with risk of MCI, MCI consistent with AD or other MCI. No statistically significant difference in the change of composite cognition and any individual cognitive domains between statin users versus non-statin users was seen. However, researchers did find interaction effects between baseline cognitive ability and statin therapy for all dementia outcomes.

The researchers acknowledged several limitations, including observational study bias and lack of data on the length of prior use of statins; and the dose of statins was not recorded in the ASPREE trial, so their effects could not be fully explored. Researchers conclude the study must be interpreted with caution and will require confirmation by randomized clinical trials designed to explore the neurocognitive effects of statins in older populations.

In an accompanying editorial comment, Christie M. Ballantyne, MD, professor at Baylor College of Medicine in Houston, noted study limitations that the authors address, but agreed the findings suggest statins do not contribute to cognitive decline.

“Overall, the analysis was well done, and its main strengths are a large cohort with a battery of standardised tests that allowed the investigators to track both cognition and incidence of dementia and its subtypes over time,” Ballantyne said. “Lingering questions such as the one raised by this analysis regarding potential adverse effects of statins in individuals with mildly impaired cognition can only be answered in randomised controlled trials in the appropriate age group and population and with appropriate testing and adequate follow-up. In the meantime, practising clinicians can have confidence and share with their patients that short-term lipid lowering therapy in older individuals, including with statins, is unlikely to have a major impact on cognition.”

Source: American College of Cardiology