Neuropsychiatric Symptoms Speed Alzheimer's Progression, Death

Liam Davenport

May 11, 2015

A range of neuropsychiatric symptoms are associated with earlier progression to severe Alzheimer's disease (AD) and earlier death, new research shows.

Using data from a landmark longitudinal study, investigators at Johns Hopkins University, in Baltimore, Maryland, found that psychotic and affective symptoms had a differential impact on the speed of progression to severe AD and death.

Nevertheless, the presence of at least one clinically significant neuropsychiatric symptom predicted progression to both outcomes.

The research is published in the May issue of the American Journal of Psychiatry.

Clinical Implications?

Led by Matthew E. Peters, MD, Department of Psychiatry, Johns Hopkins University, the researchers note that little is known about factors that influence the rate of AD progression.

To examine the link between clinically significant neuropsychiatric symptoms in patients with mild AD and progression to severe dementia or death, the investigators analyzed data from the Cache County Dementia Progression Study, in which 5092 residents aged 65 years and older were recruited in 1995 and then screened at 3- to 5-year intervals.

There were 335 cases of incident AD, occurring at a mean age of onset of 84.3 years. Sixty-eight individuals (20%) developed severe dementia during the course of the study. By 2010, 273 participants had died. The median time to severe disease was 8.4 years, and time to death was 5.7 years.

Neuropsychiatric symptoms were identified in 50.9% of patients. Psychosis cluster symptoms were diagnosed in 18.1% of patients, and affective cluster symptoms in 38.8%. The symptom apathy/indifference was observed in 16.9% of patients at baseline; 10.0% had domain agitation/aggression.

Multivariate Cox regression analysis revealed that progression to severe dementia was predicted by psychosis cluster, agitation/aggression, and at least one clinically significant neuropsychiatric symptom (hazard ratio [HR], 2.007, 2.946, and 2.682, respectively; P = .03, P = .004, and P = .001, respectively).

Progression to death was predicted by the psychosis cluster (HR = 1.537; P = .01), affective cluster (HR = 1.510; P = .003), agitation/aggression (HR = 1.942; P = .004), at least one mild neuropsychiatric symptom (HR = 1.448; P = .02), and at least one clinically significant neuropsychiatric symptom (HR = 1.951; P ≤ .001).

Time to death was also associated with worse medical health status. Age at dementia onset was related to time to severe dementia in a nonlinear fashion; it was linearly related to time to death.

The results were not affected by age at onset, health status, or the use of antidepressants, antipsychotics, or benzodiazepines. Unlike results of previous studies, apathy did not predict progression to death.

The findings complement those of a previous study by the same investigators in the same population, in which female sex, having less than a high school education, and having at least one clinically significant neuropsychiatric symptom at baseline predicted a shorter time to severe AD.

Furthermore, age at dementia onset predicted faster progression to severe dementia in both the youngest and oldest age tertiles in that study.

Discussing the findings with Medscape Medical News, Dr Peters explained that there are three potential hypotheses for how neuropsychiatric symptoms are related to dementing illness, which he and coauthor Constantine G. Lyketsos, MD, MHS, set out in an editorial earlier this year. They are as follows:

  • The symptom hypothesis, in which neuropsychiatric symptoms are thought to result from AD-related changes in the brain;

  • The risk factor hypothesis, in which neuropsychiatric symptoms are caused by concurrent pathology that is unrelated to AD pathology; and

  • The unmet needs model, in which behavioral symptoms arise because an individual or their caregiver is unable to meet his or her needs.

Dr Peters believes, however, that one of the challenges in patients with AD is in identifying neuropsychiatric symptoms, particularly those that are more "nuanced."

"I'd like to say that, in psychiatry, we're careful about looking for these...but there are a lot of patients that we end up seeing who have been treated for dementia or mild cognitive impairment for years and nobody has picked up on the fact that there's another neuropsychiatric symptom," he said.

"With these findings, although we don't know what the impact on morbidity and mortality of treating these individuals may be, the hope would be that progression would slow and that mortality would go back to the normal rate," Dr Peters added.

"But we don't know that, and when we did treat these people with medications...there wasn't a difference between those that were treated and those that had the symptoms at initial treatment."

Urgent Need to Address Progression

In an accompanying editorial, Anton P. Porsteinsson, MD, Department of Psychiatry, University of Rochester School of Medicine and Dentistry, in New York, described the Cache County study as "well-run, well-executed," and "highly respected" and noted that the findings have implications for identifying early clinical signals of accelerated disease progression.

On one hand, they may allow for the possible modulation of risk factors, and on the other hand, earlier treatment.

"As the dementia epidemic is upon us, it will be extremely important to prevent or delay progression in even some of those cases, since so much of the financial and emotional cost is realized in the more advanced stages," they write.

"We do not fully know yet whether treatment interventions or risk modifications are helpful in the short- or long-run ― this is a grand challenge that urgently needs answers."

Dr Porsteinsson told Medscape Medical News that the Cache County study is "landmark" research in terms of understanding dementia and cognitive disorders and the risks for onset and their impact on the course of AD.

Setting out the impact that neuropsychiatric symptoms have on patients with AD, Dr Porsteinsson explained that the psychotic symptoms, in particular, make it hard to care for people, whereas the affective symptoms make patients become withdrawn.

"What I mean by that is that the more distrustful, the more withdrawn you are, for example, it's very hard to provide good care," he said.

"You don't want to go to the doctors, you don't want to take pills, you don't want to do this, you don't want to do the other; when you are at the doctors, you are guarded, you are withdrawn."

"These are some of the challenging patients that I deal with in the office, let alone by a primary care physician who maybe has to put hands on them, etc."

However, Dr Porsteinsson acknowledged that the picture is made more complicated by the lack of understanding of the nature of the relationship between neuropsychiatric symptoms and dementia.

Noting the three potential hypotheses, he said: "We don't know what's the chicken and what's the egg for certainty here. Are the symptoms somehow driving the disease, or are the symptoms basically an expression of a worse disease?"

Nevertheless, the ultimate goal remains to prevent AD, and Dr Porsteinsson said that a number of studies have given a better understanding of the role of lifestyles, dietary habits, exercise, and genetics in terms of reducing the risk of developing the disease.

"On the other hand, for the large group of people that have dementia now, what we don't is, if we intervene and we treat these symptoms successfully...be that pharmacologically or nonpharmacologically, with support, with encouragement, would we have a different outcome? We don't know."

As a more near-term endeavor, Dr Porsteinsson believes that novel treatments are required for AD.

"Can we find successful treatments for these conditions? We don't have them right now; by that, I mean pharmacological treatments that are safe and well tolerated, as well as effective. We may have treatments right now that are effective, but they aren't necessarily so safe and well tolerated."

In the short term, Dr Porsteinsson emphasized that care environments need to be provided in which patients "feel less stressed, where there's attention to keeping people involved and active at the level that they can manage."

"One of the problems that I often see in Alzheimer's disease and other dementias is that you're living in a setting where basically you need to perform at a certain level to 'survive' in that setting that is higher than you can really handle," he added.

"That would be like taking a kid and putting them in classes that are too hard for them to manage. They basically fall apart, they're anxious and frustrated and don't do well at all."

Dr Porsteinsson concluded: "You have to match the expectations of the care environment to what people can manage."

The study was supported by the Cache County Memory Study, the Dementia Progression Study, and the Joseph and Kathleen Bryan Alzheimer's Disease Research Center. A full listing of relevant financial relationships is presented in the original article.

Am J Psychiatry. 2015;172:460-465, 410–411. Abstract, Editorial

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