Matt Hoffman

This article, "Dementia-Related Psychosis Places Heavy Burden on Patients and Caretakers," was originally published in NeurologyLive.

Data from a survey of patients with dementia-related psychosis and their care partners seeking to identify unmet needs in treatment and patient experience suggest that symptoms of visual hallucinations and paranoid delusions carry a high burden for both patients and their caretakers.

The data revealed that a number of patients were either not taking a treatment for their psychosis or their current therapy included adverse events and limited efficacy.

All in all, 42% of both patient and care partner respondents reported having no current treatment, with the reported agents being atypical antipsychotics, antidepressants, anxiolytics, and benzodiazepines.

The results were presented virtually at the 

Alzheimer’s Association International Conference (AAIC) 2020 annual meeting

 by Teresa Brandt, PhD, MCB, Executive Director of Regulatory Affairs, Acadia Pharmaceuticals.

The online survey included 212 patients (n = 26) and care partners (n = 186) who completed the survey on behalf of patients under their care, of which 16 partook in a qualitative interview (patients, n = 1; care partners, n = 15).

“The data shows people with dementia-related psychosis experience hallucinations and delusions that have a substantial burden on their lives,” Brandt said in a statement. “We are pleased to be a part of this patient-focused study as it is critical for the treatment triad of patients, caregivers and healthcare providers to better identify and understand these symptoms, and to incorporate the patient’s voice in drug development and evaluation.”

The most common symptoms reported by patients were visual hallucinations (89%), auditory hallucinations (54%), and a distortion of senses (54%).

Of those who reported recent visual hallucinations, 61% noted that they occurred weekly.

Additionally, the participants described an impact of dementia-related psychosis on their activities of daily living (75%), sleep (63%), family life (56%), and as well as safety concerns (56%).

The care partners, on the other hand, reported that paranoid delusions (76%), visual hallucinations (75%), and lack of trust for loved ones (52%) were the most common symptoms experienced by their patient partners. In total, 77% of the care partners reported paranoid delusions as occurring at least weekly.

“The symptoms of dementia-related psychosis can cause fear and anxiety, disrupting the lives of people living with dementia and their families,” said Virginia Biggar, Senior Director of Communities, UsAgainstAlzheimer’s, in a statement.

The survey participants noted that in many cases, their current treatment method was less than helpful, with a median visual analog scale (VAS) score of 2 out of 5 (patients: mean score, 2.33 [standard deviation (SD), 1.0]; care partners: mean score, 2.4 [SD, 1.3]).

The most common reason for discontinuation of a treatment—reported by 11 patients and 115 partners—was an adverse effect, reported by 27% and 31% of patients and partners, respectively.

The next most common reasons were physician recommendation (patients: 27%; care partners: 14%), and lack of symptom improvement (patients: 9%; care partners: 28%).

All told, when queried about what an ideal treatment would provide for them, patients and care partners ranked the ability to distinguish reality (patients: 35%; care partners: 49%) and overall symptom improvement (patients: 42%; care partners: 23%) as the most important benefits.

“The survey results show that many patients with dementia-related psychosis are unaware of what’s happening or how to communicate what they are experiencing. The findings highlight the need for caregivers and healthcare providers to be able to better recognize, report, and manage these symptoms,” Terry Frangiosa, lead investigator, A-LIST Insight Series, UsAgainstAlzheimer’s, said in a statement.

Additional data presented at AAIC 2020 suggest that a treatment may be on the way, with the results of the phase 3 HARMONY study demonstrating that treatment with pimavanserin produced a robust reduction in psychosis symptoms, irrespective of most likely clinical diagnosis of dementia subtype or baseline dementia severity.

 for such an indication, the application being supported by the HARMONY data. Its prescription drug user fee act (PDUFA) date was set for April 3, 2021.

Articles

In a pair of studies, 42% of patients and care partners reported having no current treatment.

 Dementia-Related Psychosis a Burden for Both Patients and Caretakers

This article, "Influenza, Pneumonia Vaccination May Reduce Alzheimer Disease Risk," was originally published in NeurologyLive.

Influenza and pneumonia vaccinations could help reduce the incidence of Alzheimer disease dementia, according to new findings from a number of studies presented virtually at the 

A trio of studies suggest that more frequent flu vaccination was associated with a 13% reduction in the incidence of Alzheimer, while vaccination between the ages of 65 and 75 years was linked to a gene-dependent reduction of Alzheimer by up to 40%.

Additionally, the third study using data from a large clinical database implied that 1 influenza vaccination reduced the incidence of Alzheimer by 17%.

Notably, the work by Janet Janbek, PhD student, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, et al. found that mortality risk was twice as high—a 6-fold total increase—for those with dementia after infections compared to those without dementia after infection, which led to a 3-fold increase.

“With the COVID-19 pandemic, vaccines are at the forefront of public health discussions. It is important to explore their benefit in not only protecting against viral or bacterial infection but also improving long-term health outcomes,” said Maria C. Carrillo, PhD, chief science officer, Alzheimer’s Association, in a statement.

“It may turn out to be as simple as if you’re taking care of your health in this way—getting vaccinated—you’re also taking care of yourself in other ways, and these things add up to lower risk of Alzheimer’s and other dementias.”

Janbek and colleagues found, using data from Danish national registries, that the mortality rate ratios (MRRs) for those with dementia was 6.52 (95% CI, 6.43–6.61) times higher post-infection than the reference group.

The MRRs were the highest within the first 30 days of infection in those with dementia and remained elevated compared to those without dementia until 10 years after first infection.

Their registry included 1,496,346 people (12,739,135 person-years), of which 575,260 died during follow-up (82,573 of whom had dementia). Janbek noted in a statement that the study supports the need to assess the relationships and why those with dementia seem to be more greatly impacted.

“Our study suggests that the health care system—as well as relatives of people with dementia—should have increased awareness of people with dementia who get infections, so they get the medical care they need,” Janbek said. “People with dementia require more specialized treatment even when their hospital visits are not directly due to their dementia but to what might appear to be an unrelated infection.”

The work conducted by Albert Amran, medical student, McGovern Medical School, University of Texas Health Science Center, and colleagues, utilized an electronic health record dataset that included patients over the aged 60 years and older, including those with Alzheimer disease (n = 311,424), using propensity score matching to obtain a balanced set of vaccinated and unvaccinated patients (n = 9066).

Then, they used chi-square test, uni-variate analysis, and time-to-event analysis to get their results.

Ultimately, what they found was that an influenza vaccine significantly decreased the prevalence of Alzheimer (odds ratio [OR], 0.8309; 

 <.0001), and the frequency of influenza vaccination can have a marked impact to prevent the onset of Alzheimer (OR, 0.8736; 

As well, Amran et al. found through time-to-event analysis that earlier-age vaccination led to a lower risk for Alzheimer than later-age vaccination (hazard ratio [HR] increased by 1.0924 per 1 year of age at first vaccination; 

Those who consistently got annual flu shots decreased their risk, translating to an almost 6% reduction between the ages of 75–84 years.

“Our study suggests that regular use of a very accessible and relatively cheap intervention—the flu shot—may significantly reduce risk of Alzheimer’s dementia. More research is needed to explore the biological mechanism for this effect—why and how it works in the body—which is important as we explore effective preventive therapies for Alzheimer’s,” Amran said in a statement.

Svetlana Ukraintseva, PhD, associate research professor, Biodemography of Aging Research Unit (BARU), Duke University Social Science Research Institute, and team, assessed the associations between Alzheimer and pneumococcal vaccination, with and without a seasonal influenza vaccination, in the third work.

They used a cohort of patients aged 65 years and older (n = 5146) from the Cardiovascular Health Study.

They found that having pneumococcal vaccination between the ages of 65 and 75 years could reduce Alzheimer risk by 25% to 30% after adjusting for confounding factors (OR, 0.70; 

The total number of vaccinations was also associated with a lower risk of Alzheimer later in life (OR, 0.88; 

 <.01), though this was not observed with solely the flu vaccine.

Additionally, they assessed the presence of the rs2075650 G allele in the TOMM40 gene, a known genetic risk factor for Alzheimer. The largest reduction of risk—up to 40%—was observed for those who did not carry the allele (OR, 0.62; 

“This research, while early, calls for further studies in large, diverse clinical trials to inform whether vaccinations as a public health strategy decrease our risk for developing dementia as we age,” Carrillo noted in a statement.

Three studies presented during the AAIC 2020 annual meeting show how frequent influenza vaccination help promote a gene-dependent reduction of Alzheimer disease by up to 40%.

Flu and Pneumonia Vaccines Could Help Reduce Alzheimer Disease Dementia Risk

This article, "Less REM Sleep Associated With Higher Mortality Risk in Older Adults," was originally published in NeurologyLive.

 could increase the mortality risk for older adults, according to a new study.

An analysis of a cross-sectional study of more than 4000 patients from the Outcomes of Sleep Disorders in Older Men Sleep Study (MrOS; n = 2675) and Wisconsin Sleep Cohort (WSC; n = 1386) suggests that lower amounts of rapid eye movement (REM) sleep is associated with an increased risk of all-cause mortality in middle-aged and older adults.

Ultimately, over the 12.1-year period of the MrOS study, which began in 2003, there was a 13% higher mortality rate for every 5% reduction in REM sleep, which was confirmed with the second cohort in the 20.8 years of the WSC study, which began in 1988.

The study was conducted by a group of researchers including Eileen B. Leary, PhD, RPSGT, clinical scientist, Jazz Pharmaceuticals.

“A robust association was found between percentage of REM sleep and mortality in 2 independent cohorts, which persisted across different causes of death and multiple sensitivity analyses. Given the complex underlying biologic functions, further studies are required to understand whether the relationship is causal,” the authors wrote.

They noted that accelerated brain aging may be a better marker than risk factor for mortality as it could be a cause of less REM sleep, though studies will need to confirm this.

“Strategies to preserve REM sleep may influence clinical therapies and reduce mortality risk, particularly for adults with less than 15% REM,” Leary and colleagues concluded.

In an accompanying editorial, Michael S. Jaffee, MD; Liza H. Ashbrook, MD; and Milena K. Pavlova, MD, wrote that while these data do not imply a causal relationship, the neurologist community should be aware of them, as it brings into question the possibility that REM sleep could serve as a general health biomarker.

“Fundamentally, our understanding of the function of REM sleep is still incomplete. In recent years, the role of REM sleep in memory consolidation and synaptic remodeling and pruning has become [clearer],” the authors wrote.

They clarified since the understood roles of REM sleep do not clearly suggest there is a causal link with mortality, “it seems more likely that REM sleep reduction is either a crude marker of health or specific disease states that decrease REM sleep may play an important role in contributing to mortality.”

The MrOS cohort was 100% men, with a mean age of 76.3 years (standard deviation [SD], 5.5), of which 91.5% (n = 2448) were white. They were followed for a median of 12.1 years (interquartile range [IQR], 7.8—13.2). The WSC cohort was 54.3% men (n = 753), with a mean age of 51.5 years (SD, 8.5), of which 94.6% (n = 1311) were white. They were followed for a median of 20.8 years (IQR, 17.9–22.4).

In MrOS, the percentage of REM sleep varied from 0% to 43.9% and was normally distributed. The total mean percentage of REM sleep was 19.2% (SD, 6.6%) with a mean time in REM sleep of 69.7 minutes (SD, 28.6).

From the lowest quartile to the highest, those values increased from 14.8% to 23.6% (quartile 1: <14.8% REM, n = 677; quartile 2: 14.8%—19.4% REM, n = 662; quartile 3: 19.5%–23.5% REM, n = 667; quartile 4: >23.6% REM, n = 669).

There were 1404 deaths (52.5%) over the follow-up period in MrOS, with a 13% higher all-cause mortality rate for every 5% reduction in REM sleep (hazard ratio [HR], 1.13; 95% CI, 1.08—1.19) after adjusting for covariates.

Cardiovascular disease-related mortality continued this association (HR, 1.11; 95% CI, 1.02—1.20), as did other mortality (HR, 1.19; 95% CI, 1.11–1.28). Cancer-related mortality was not significantly altered by lower REM (HR, 1.06; 95% CI, 0.96–1.17). Those with <15% REM sleep had a higher mortality rate compared with those with ≥15% for all mortality definitions (HR range, 1.20–1.35).

For the WSC cohort, the mean number of minutes in REM sleep was 67.8 (SD, 28.9) and a percentage of REM sleep range of 0% to 43.0%, similar to the MrOS cohort.

Although the overall mean percentage of REM sleep was lower (mean, 17.6% [SD, 6.5%]). From the lowest to highest quartiles, the values increased from 13.3% to 21.8% (quartile 1: <13.3% REM, n = 345; quartile 2: 13.3%—17.5% REM, n = 348; quartile 3: 17.6%–21.7% REM, n = 347; quartile 4: >21.8% REM, n = 346).

In part due to the younger age of the WSC group, there were fewer deaths (184 [13.3%]). For a 5% reduction in REM sleep, the effect size on the risk of all-cause mortality was also significant (HR, 1.17; 95% CI, 1.03—1.34).

This was also the case for and non-cardiovascular disease and non-cancer-related mortality (HR, 1.26; 95% CI, 1.01—1.58), despite the inclusion of both men and women, longer follow-up period, reduced samples size, and event frequency.

For cardiovascular disease-related mortality and cancer-related mortality, the findings were also similar, though with wider confidence intervals (cardiovascular: HR, 1.13 [95% CI, 0.87—1.45]; cancer: HR, 1.13 [95% CI, 0.91–1.40]).

Those with <15% REM sleep had a higher mortality rate compared with individuals with ≥15% (OR range, 1.36 to 1.78) for all mortality definitions saver for cardiovascular (HR, 1.00; 95% CI, 0.52—1.90).

“Sensitivity analyses showed findings persisted in subgroups with sleep duration between 5—8 and 6–8 hours (except cancer), without depression, severe sleep apnea, and in those not using medications that may affect REM,” the authors wrote. “In sum, decreased REM sleep was an indicator of mortality risk across a broad age range, which is consistent with the study evaluating REM sleep and mortality in the Sleep Heart Health Study. When stratified by sex, there was a higher rate of all-cause mortality in women compared with men.”

New research finds a 13% higher mortality rate for every 5% reduction in REM sleep.

More REM Sleep Needed to Reduce Mortality Rate in Older Adults

At the 36th annual meeting of the American Society of Retinal Specialists (ASRS) in Vancouver, British Columbia, MD Mag sat with Steven Yeh, MD, to talk about the findings of the phase 3 PEACHTREE trial, which he presented at the meeting.

Yeh spoke about the utilization of a hollow micro-needle to deliver corticosteroid medicines in the suprachoroidal space, in place of intravitreal or periocular injections, which can often lead to a dangerous increase in intraocular pressure. This method was utilized in the PEACHTREE study, which enrolled 160 patients, 96 of which were randomized to the treatment arm to receive a pair of 4.0 mg doses of suprachoroidal suspension of the corticosteroid triamcinolone acetonide (CLS-TA) 12 weeks apart, and 64 patients of which were randomized to undergo sham procedures at the same 12-week interval. The patients were evaluated every 4 weeks for a total of 24 weeks, and 97% (n = 155) of those enrolled saw the full evaluation period to completion.

The mean change from baseline in the CLS-TA arm was an improvement of 9.6 letters at week 4 and 13.7 letters at week 24, as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) score. In comparison, the control arm improved 1.2 letters and 2.9 letters at those respective time points. 

In a secondary endpoint, the administration of suprachoroidal CLS-TA resulted in an average reduction of 157 microns in central subfield thickness from baseline at week 24, compared to a 19-micron reduction in the sham cohort (

The primary mode of delivery for corticosteroids to the eye is either directly into the eye as an intravitreal injection or outside the eye, in what's called a periocular injection. But we know that, particularly in uveitis patients, that with intravitreal corticosteroids, the rates of corticosteroid-associated elevations in eye pressure—intraocular pressure&mdash;can vary anywhere from 25% to as high as 90%, with some corticosteroid delivery systems.

So the thought that, again, through leading work done by [the late] Henry Edelhauser, PhD, at Emory University and Georgia Tech by Mark Prausnitz, PhD—the theory was that using a hollow microneedle, medication could be delivered into this potential space for the first time, and essentially give high levels of drug to the areas that mattered the most. These were areas like the retina, the retinal pigment epithelium, and the choroid for this disease indication [of macular edema associated with non-infectious uveitis].

So there was quite a bit of basic science work that actually showed that this was feasible, and this was found to be true in phase 1 and phase 2 trials, where suprachoroidal medication was able to be delivered and also the patients were able to derive benefit, as well, from this medication.

The PEACHTREE study was a phase 3, multicenter, randomized, controlled trial that looked at the delivery of suprachoroidal CLS-TA for the treatment of non-infectious uveitis in patients who had macular edema, or retinal swelling. The primary metric for patients who were treated with 2 injections of CLS-TA at the day 0 and the week 12 time point was the ability to improve visual acuity by 3 lines of vision or greater. What we found in the patients who were treated with CLS-TA was that 47% of patients were able to achieve 3 lines or better of visual acuity, when compared to 15% of the patients who received sham treatment (

Besides the efficacy signals, which were very encouraging, we also looked at safety in the PEACHTREE study, and what we found was that when we looked at intraocular pressure elevation when patients were receiving suprachoroidal CLS-TA, intraocular pressure was actually very favorable in the study. When we think about the way that we deliver corticosteroids for the treatment of non-infectious uveitis, in the literature and in clinical practice, there can significant rates of intraocular pressure elevation with the currently available corticosteroid delivery mechanisms, including both the clinically-based procedures as well as the surgical procedures. The rates of corticosteroid-associated elevations intraocular pressure, [again] range from 25% to 90%, which is quite high. Becuase of that, we feel that CLS-TA, because of its lower rate of the rates of corticosteroid-associated intraocular pressure,  has definite potential in the future for the treatment of macular edema associated with non-infectious uveitis, both due to its efficacy and the safety profile.

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Patients who were treated with CLS-TA were able to achieve ≥3 lines of visual acuity 47% of the time, compared to 15% of the patients who received sham treatment.

Author | Matt Hoffman

Articles

Dementia-Related Psychosis a Burden for Both Patients and Caretakers

Flu and Pneumonia Vaccines Could Help Reduce Alzheimer Disease Dementia Risk

More REM Sleep Needed to Reduce Mortality Rate in Older Adults

Suprachoroidal CLS-TA Proves Effective, Safe in PEACHTREE Trial