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Dementia/Sleep Aids-Drugs/Women HIV+ More Vulnerable - "Sleep aids and dementia: Studies find both risks and benefits"
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Reported from the 2019 Alzheimers Association International conference, Los Angels July 14-18
"white subjects who reported taking sleep aids five or more times a month at baseline had a nearly 80% higher risk of developing dementia during the course of the study (hazard ratio, 1.79; 95% confidence interval, 1.21-2.66), compared with people who reported never taking sleep aids or taking them less frequently.
I don't think we will ever have a magic bullet," Dr. Karageorgiou said. "Because when our brain degenerates, it's not just one chemical, or one system, it's many. And our body changes as well. The important thing is to help the patient consolidate their rhythms, whether through light therapy, daily exercise, cognitive behavioral therapy for insomnia, or other evidence-based interventions and their combination. The same applies for a person with dementia as for the rest of us."
Report below but first some background in HIV+ women studied in WIHS....
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"Women with HIV May Be More Cognitively Vulnerable than Men with HIV"
Differences in Cognitive Function Between Women and Men With HIV [JAIDS 2018]- "Cognitive function was examined in a large sample women from the WIHS (n = 710) and men (n = 710) from the MACS-the 2 longest-running longitudinal studies of HIV disease progression in the United States. We found evidence to support the hypothesis that HIV+ women compared with HIV+ men show cognitive vulnerabilities in aspects of psychomotor speed, attention, processing speed, and motor skills. To determine whether those differences were clinically significant, we also examined sex differences in the odds of scoring in the impaired range. We found that compared with HIV+ men, HIV+ women had a higher odds of scoring in the impaired range in psychomotor speed and attention (TMTA) and motor skills (GP). Previous studies demonstrate some of the factors that may contribute to these findings of a female disadvantage across cognitive measures. We controlled for depression in this study, but other mental health factors that are not available in the MACS have been shown to negatively influence cognitive function in HIV+ women, including stress and post-traumatic stress disorder.21,22,25 Previous studies show that these psychological factors affected cognitive function in HIV+ women more than HIV− women.21,22 Although we controlled for recent substance use in this study, a more thorough examination of substance use is warranted. In the WIHS, cocaine and heroin use had a greater influence on cognition in HIV+ women compared with HIV− women, an effect that was associated with alterations in prefrontal function. Recent work shows an interactive effect of sex and HIV on cognition among substance-dependent individuals, with HIV+ women showing poorer cognitive function compared with other groups.26-28 Finally, these effects may also reflect the influence of menopause20 and sexual dimorphism in immune function,29 pathogenesis,30 and/or antiretroviral pharmacokinetics.31 These possibilities will be addressed in the ongoing studies of WIHS and MACS. Overall, our results show that cognitive findings from HIV+ men cannot be uncritically generalized to HIV+ women, and that instead sex should be considered in studies of the pathogenesis, clinical presentation, and treatment of cognitive dysfunction in HIV."
AND research presented at 2018 Aging Workshop in NYC:
Older age raises odds of amnestic mild cognitive impairment (but not HAND) with HIV - by 5% per year of aging - (09/19/18)
"Every additional year of age raised odds of amnestic mild cognitive impairment (aMCI) 5% in a study of 244 people with HIV infection [1]. But older age did not affect chances of HIV-associated neurocognitive disorder (HAND) in people without aMCI. Levels of two inflammatory markers--TNF-alpha and MCP-1--were higher in older people with aMCI. Amnestic mild cognitive impairment (aMCI) is marked by memory loss but not more severe symptoms of Alzheimer's disease, such as personality changes [2]. People with aMCI may often lose things or forget appointments. ("Amnestic" refers to amnesia.) Cognitive and functional decline is characteristic of aMCI, while HAND is relatively stable."
Cognitive aging in the era of effective antiretrovirals - (09/19/18)
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WIHS HIV+ Women
"One common HIV-associated non-AIDS comorbidity is cognitive impairment, which is reported to occur in approximately 30%-60% of people with HIV at some point during their lifetime.4 The clinical features of HIV-associated cognitive impairment commonly include alterations in executive function, complex attention, processing speed, learning, and memory5-9 and these deficits are associated with dysfunction of frontostriatal networks10 and altered integrity of hippocampal and prefrontal brain regions.11-13 Interestingly, the utilization of non-ARV medications with known cognitive adverse effects may in part explain some of the cognitive complications among HIV-infected (HIV+) individuals, particularly among those individuals aged 50 years and older.......Many of the non-ARV medications used among HIV+ individuals have known cognitive adverse effects (termed "NC-AE medications").....especially agents with anticholinergic properties14-18 as well as opioids,19 anxiolytics,20 and anticonvulsants.21 This is particularly concerning because older adults in general have an increased vulnerability to medication side effects due to the pharmacokinetic and pharmacodynamic changes that occur with aging.22 For example, with age, metabolism and drug elimination slows, the blood-brain barrier changes, and there are age-related deficits in neurotransmission.23 As a result, many medications with higher side effect burden are not routinely recommended in older patients
.......To the best of our knowledge, this is the first study to examine the general effects of non-ARV NC-AE medications as well as the effects of commonly used non-ARV classes of medications such as anticholinergics, opiates, anticonvulsants, and anxiolytics with known neurocognitive effects on cognitive performance in a sample of HIV+ and HIV- women. Although we demonstrated that non-ARV NC-AE medications are more commonly used among HIV+ compared with HIV- women, differential usage of these non-ARV medications does not seem to explain greater cognitive impairment among HIV+ compared with HIV- women. However, greater use of non-ARV medications with anticholinergic properties as well as anxiolytics/anticonvulsants and opioids among HIV+ vs. HIV- women may in part explain some of the greater cognitive impairment among HIV+ compared with HIV- women, particularly on global function, learning, fluency, psychomotor speed, and motor function."
WIHS:
Cognitive Burden of Common Non-antiretroviral Medications in HIV-Infected Women (WIHS)
HIV+ women have increased cognitive vulnerabilities to anticholinergic, anxiolytic/anticonvulsant, and opioid medications. Potential synergy between these medications and HIV may explain some HIV-related cognitive impairments. It may be important clinically to consider these specific types of medications as a contributor to impaired cognitive performance in HIV+ women and assess the cost/benefit of treatment dosage for underlying conditions.
Anticholinergic drugs fall into many different classes of drugs, so it's hard for patients to identify or remember these specific drugs. For example, some antihistamines, antidepressants, or even muscle relaxants have anticholinergic properties. Patients with delirium, dementia, constipation, and benign prostatic hypertrophy (BPH) are particularly at risk of anticholinergic adverse drug events. Refer to the list below for a list of anticholinergic drugs to avoid in older patients. The results of this study showed that the current use of drugs with anticholinergic properties was significantly associated with low cognitive performance among community-dwelling elderly people
http://www.natap.org/2018/HIV/091118_01.htm
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Sleep aids and dementia: Studies find both risks and benefits
Publish date: August 7, 2019
By
Jennie Smith
Clinical Neurology News
https://www.mdedge.com/clinicalneurologynews/article/206002/alzheimers-cognition/sleep-aids-and-dementia-studies-find-both
"white subjects who reported taking sleep aids five or more times a month at baseline had a nearly 80% higher risk of developing dementia during the course of the study (hazard ratio, 1.79; 95% confidence interval, 1.21-2.66), compared with people who reported never taking sleep aids or taking them less frequently.
I don't think we will ever have a magic bullet," Dr. Karageorgiou said. "Because when our brain degenerates, it's not just one chemical, or one system, it's many. And our body changes as well. The important thing is to help the patient consolidate their rhythms, whether through light therapy, daily exercise, cognitive behavioral therapy for insomnia, or other evidence-based interventions and their combination. The same applies for a person with dementia as for the rest of us."
Chris Fox, MD, a researcher at the University of East Anglia in Norwich, England, and his colleagues demonstrated in 2018 that long-term exposure to anticholinergic drugs, a class that includes some antidepressants and antihistamines used to promote sleep, was associated with a higher risk of dementia, while use of benzodiazepines, a class of sedatives used commonly in older people as sleep aids, was not.
Dr. Fox and his colleagues found that, while neither anticholinergic nor benzodiazepine exposure was associated with brain pathology specific to that seen in Alzheimer's disease, both classes of drugs were associated with "slight signals in neuronal loss" in one brain region, the nucleus basalis of Meynert. Dr. Fox described the drugs as causing "an increase in cognitive aging" which could bear on Alzheimer's risk without being directly causative.
The investigators, led by doctoral student Elizabeth Vernon, found that men reporting use of sleep medication saw more than threefold higher risk of developing Alzheimer's disease than did men who did not use sleep aids (HR, 3.604; P = .0001).
Women who did not report having sleep disturbance but used sleep-inducing medications were at nearly fourfold greater risk for developing Alzheimer's disease (HR, 3.916; P = .0001). Women who self-reported sleep disturbances at baseline, meanwhile, saw a reduction in Alzheimer's risk of about one-third associated with the use of sleep medications......despite the finding of risk reduction for this particular group of women, caution in prescribing sleep aids was warranted."
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REPORTING FROM AAIC 2019
LOS ANGELES - While a large number of older adults take prescription and nonprescription medications to help them sleep, the effect of these medications on dementia risk is unclear, with most researchers advocating a cautious and conservative approach to prescribing.
Research is increasingly revealing a bidirectional relationship between sleep and dementia. Poor sleep - especially from insomnia, sleep deprivation, or obstructive sleep apnea - is known to increase dementia risk. Dementias, meanwhile, are associated with serious circadian rhythm disturbances, leading to nighttime sleep loss and increasing the likelihood of institutionalization.
At the Alzheimer's Association International Conference, researchers presented findings assessing the links between sleep medication use and dementia and also what agents or approaches might safely improve sleep in people with sleep disorders who are at risk for dementia or who have been diagnosed with dementia.
Yue Leng, PhD, of the University of California, San Francisco, reported a link between frequent sleep medication use and later dementia - but only in white adults. Dr. Leng presented findings from the National Institutes of Health-funded Health, Aging, and Body Composition Study, which recruited 3,068 subjects aged 70-79 and followed them for 15 years. At baseline, 2.7% of African Americans and 7.7% of whites in the study reported taking sleep medications "often" or "almost always."
Dr. Leng and her colleagues found that white subjects who reported taking sleep aids five or more times a month at baseline had a nearly 80% higher risk of developing dementia during the course of the study (hazard ratio, 1.79; 95% confidence interval, 1.21-2.66), compared with people who reported never taking sleep aids or taking them less frequently.
The researchers saw no between-sex differences for this finding, and adjusted for a variety of genetic and lifestyle confounders. Importantly, no significant increase in dementia risk was seen for black subjects, who made up more than one-third of the cohort.
Dr. Leng told the conference that the researchers could not explain why black participants did not see similarly increased dementia risk. Also, she noted, researchers did not have information on the specific sleep medications people used: benzodiazepines, antihistamines, antidepressants, or other types of drugs. Nonetheless, she told the conference, the findings ratified the cautious approach many dementia experts are already stressing.
"Do we really need to prescribe so many sleep meds to older adults who are already at risk for cognitive impairment?" Dr. Leng said, adding: "I am a big advocate of behavioral sleep interventions." People with clinical sleep problems "should be referred to sleep centers" for a fuller assessment before medication is prescribed, she said.
Findings from another cohort study, meanwhile, suggest that there could be sex-related differences in how sleep aids affect dementia risk. Investigators at Utah State University in Logan used data from some 3,656 older adults in the Cache County Study on Memory and Aging, an NIH-backed cohort study of white adults in Utah without dementia at baseline who were followed for 12 years.
The investigators, led by doctoral student Elizabeth Vernon, found that men reporting use of sleep medication saw more than threefold higher risk of developing Alzheimer's disease than did men who did not use sleep aids (HR, 3.604; P = .0001).
Women who did not report having sleep disturbance but used sleep-inducing medications were at nearly fourfold greater risk for developing Alzheimer's disease (HR, 3.916; P = .0001). Women who self-reported sleep disturbances at baseline, meanwhile, saw a reduction in Alzheimer's risk of about one-third associated with the use of sleep medications.
Ms. Vernon told the conference that, despite the finding of risk reduction for this particular group of women, caution in prescribing sleep aids was warranted.
Common sleep drugs linked to cognitive aging
Chris Fox, MD, a researcher at the University of East Anglia in Norwich, England, and his colleagues demonstrated in 2018 that long-term exposure to anticholinergic drugs, a class that includes some antidepressants and antihistamines used to promote sleep, was associated with a higher risk of dementia, while use of benzodiazepines, a class of sedatives used commonly in older people as sleep aids, was not. (Whether benzodiazepine exposure relates to dementia remains controversial.)
At AAIC 2019, Dr. Fox presented findings from a study of 337 brains in a U.K. brain bank, of which 17% and 21% came from users of benzodiazepines and anticholinergic drugs, whose usage history was well documented. Dr. Fox and his colleagues found that, while neither anticholinergic nor benzodiazepine exposure was associated with brain pathology specific to that seen in Alzheimer's disease, both classes of drugs were associated with "slight signals in neuronal loss" in one brain region, the nucleus basalis of Meynert. Dr. Fox described the drugs as causing "an increase in cognitive aging" which could bear on Alzheimer's risk without being directly causative.
Newer sleep drugs may help Alzheimer's patients
Scientists working for drug manufacturers presented findings on agents to counter the circadian rhythm disturbances seen in people with Alzheimer's disease. Margaret Moline, PhD, of Eisai in Woodcliff Lake, N.J., showed some results from a phase 2, dose-ranging, placebo-controlled study of the experimental agent lemborexant in 62 subjects aged 60-90 with mild to moderate Alzheimer's disease and sleep disturbances. (Lemborexant, an orexin receptor agonist that acts to regulate wakefulness, is being investigated in a broad range of sleep disorders.) Patients were randomized to one of four doses of lemborexant or placebo and wore a device for sleep monitoring. Nighttime activity indicating arousal was significantly lower for people in two dosage arms, 5 mg and 10 mg, compared with placebo, and treatment groups saw trends toward less sleep fragmentation and higher total sleep time, Dr. Moline told the conference.
Suvorexant (Belsomra), the only orexin receptor antagonist currently licensed as a sleep aid, is also being tested in people with Alzheimer's disease. At AAIC 2019, Joseph Herring, MD, PhD, of Merck in Kenilworth, N.J., presented results from a placebo-controlled trial of 277 patients with Alzheimer's disease and insomnia, and reported that treatment with 10 or 20 mg of suvorexant over 4 weeks was associated with about an extra half hour of total nightly sleep, with a 73-minute mean increase from baseline, compared with 45 minutes for patients receiving placebo (95% CI, 11-45; P less than .005).
Trazodone linked to slower cognitive decline
An inexpensive antidepressant used in low doses as a sleep aid, including in people with Alzheimer's disease, was associated with a delay in cognitive decline in older adults, according to results from a retrospective study. Elissaios Karageorgiou, MD, PhD, of the University of California, San Francisco, and the Neurological Institute of Athens presented results derived from two cohorts: patients enrolled at the UCSF Memory and Aging Center and women enrolled in the Study for Osteoporotic Fractures (SOF) in Women. The investigators were able to identify trazodone users in the studies (with two or more contiguous study visits reporting trazodone use) and match them with control patients from the same cohorts who did not use trazodone.
Trazodone was studied because previous research suggests it increases total sleep time in patients with Alzheimer's disease without affecting next-day cognitive performance.
Trazodone-using patients in the UCSF cohort (n = 25) saw significantly less decline in Mini Mental State Exam (MMSE) scores over 4 years, compared with nonusers (0.27 vs. 0.70 points per year; P = .023), an effect that remained statistically significant even after adjusting for sedative and stimulant use and the expected progression of Alzheimer's disease pathology. Importantly, the slower decline was seen only among subjects with sleep complaints at baseline and especially those whose sleep improved over time, suggesting that the cognitive benefit was mediated by improved sleep.
In the SOF cohort of 46 trazodone users matched with 148 nonusers, no significant protective or negative effect related to long-term trazodone use was found using the MMSE or the Trails Making Test. In this analysis, however, baseline and longitudinal sleep quality was not captured in the group-matching process, neither was the use of other medications. The patient group was slightly older, and all patients were women.
Dr. Karageorgiou said in an interview that the link between improved sleep, trazodone, and cognition needs to be validated in prospective intervention studies. Trazodone, he said, appears to work best in people with a specific type of insomnia characterized by cortical and behavioral hyperarousal, and its cognitive effect appears limited to people whose sleep improves with treatment. "You're not going to see long-term cognitive benefits if it's not improving your sleep," Dr. Karageorgiou said. "So, whether trazodone improves sleep or not in a patient after a few months can be an early indicator for the clinician to continue using it or suspend it, because it is unlikely to help their cognition otherwise."
He stressed that physicians need to be broadly focused on improving sleep to help patients with, or at risk for, dementia by consolidating their sleep rhythms.
"Trazodone is not the magic bullet, and I don't think we will ever have a magic bullet," Dr. Karageorgiou said. "Because when our brain degenerates, it's not just one chemical, or one system, it's many. And our body changes as well. The important thing is to help the patient consolidate their rhythms, whether through light therapy, daily exercise, cognitive behavioral therapy for insomnia, or other evidence-based interventions and their combination. The same applies for a person with dementia as for the rest of us."
None of the investigators outside of the industry-sponsored studies had relevant disclosures.
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