Dementia in Later Years an Independent Risk Factor for Death

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Medscape Today
Fran Lowry

Having dementia in later life more than doubles the risk of death, and this risk is independent of known midlife sociodemographic and cardiovascular risk factors, according to a new prospective historical study published in the January issue of the American Journal of Geriatric Psychiatry.




"This study is suggesting that dementia per se kills," lead author Michal Beeri, PhD, from Mount Sinai School of Medicine in New York City, told Medscape Medical News.



"Our original hypothesis was that one of the reasons why demented people die more and faster is because they have a bunch of other risk factors that increase their mortality, but we are finding that that is not the case."



The aim of the study was to compare the mortality rates of elderly patients with and without dementia and the differential association of midlife risk factors with mortality according to dementia status.



Study participants were drawn from a large study of 10,059 male Jewish civil servants who participated in the Israel Ischemic Heart Disease study, which began in 1963. In 1999 and 2000, 1713 of the surviving participants were evaluated for dementia and for midlife sociodemographic and cardiovascular risk factors, late-life dementia (dementia occurring older than age 65 years), and mortality.



During a period of 6 years, 718 of the participants died (42%); of the 307 participants with dementia, 71.8% died, and of the 1407 patients without dementia, 35.4% died.



On multivariate survival analysis, patients with dementia had a hazard ratio (HR) for mortality of 2.27 compared with patients without dementia (95% confidence interval [CI], 1.92 - 2.68). The study also found that other risk factors associated with mortality were socioeconomic status (HR, 0.94; 95% CI, 0.88 - 1.00), higher systolic blood pressure (HR, 1.16 per 20 mm Hg; 95% CI, 1.06 - 1.28 mm Hg), higher diastolic blood pressure (HR, 1.15 per 10 mm Hg, 95% CI, 1.06 - 1.25 mm Hg), and ever smoking (HR, 1.38; 95% CI, 1.18 - 1.61).



However, midlife total cholesterol was not associated with mortality.



Moreover, none of the interactions of the risk factors with dementia was significant.



"You would assume that those cardiovascular risk factors that were measured in midlife would be associated with mortality 35 years later, so people who had high blood pressure, higher systolic, low sociodemographic status, higher diastolic, and having ever smoked had higher mortality in this study, which is what everybody else has shown too," Dr. Beeri said.



"But when you try and see an interaction, whether the fact that you have high blood pressure and dementia is what is increasing your risk of death, you don't find that."



Dr. Beeri also emphasized that her study does not have information on the cause of death. She hopes that this information will be forthcoming in another upcoming study.



However, she added, this research demonstrates that "midlife risk factors associated with increasing mortality, including in our study, were not the explanation for the increased death of demented people," she said.



Confirmatory Findings



The fact that people with dementia are at increased risk for mortality is something that is well known and has been well known for a long time, said David Knopman, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, who was asked by Medscape Medical News to comment on the findings.



"The diagnosis of dementia definitely has a large impact on survival. That's well known. It roughly halves survival rate in older people. The issue about this paper is that these researchers looked at midlife cardiovascular risk factors and found that there was not an interaction between the presence of the cardiovascular risk factors and dementia — that having had hypertension or diabetes or smoking in midlife didn't make the mortality rate rise or reduce the survival for dementia additionally," said Dr. Knopman, who is also deputy editor of Neurology and a fellow of the American Academy of Neurology.



The fact that dementia in and of itself is associated with a greater mortality risk has been repeatedly demonstrated in many studies.



"A clinical diagnosis of Alzheimer's disease is associated with about a halving of the survival rate. If you have vascular dementia from a stroke, and have cognitive impairment or meet criteria for vascular dementia, that's even worse in terms of survival, so this is pretty well known. I would say that this study confirms what we already know," Dr. Knopman said.



Dr. Beeri and Dr. Knopman have disclosed no relevant financial relationships

Alzheimer's CSF Test: Useful or Useless?: The Future

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Medscape Today

Andrew Wilner, MD

When a disease-modifying therapy becomes available, early diagnosis of Alzheimer's disease and diagnostic testing will be enthusiastically embraced by patients and neurologists. At that point, the relative advantages and disadvantages, including patient comfort and cost, of CSF testing and other diagnostic testing for Alzheimer's disease, such as genetic testing, neuropsychological testing, and neuroimaging, including magnetic resonance imaging of the temporal lobes, 2-deoxy-2-[F-18] fluoro-D-glucose Positron Emission Tomography (FDG-PET), amyloid radioligand Pittsburgh compound B (PiB), single photon emission computed tomography (SPECT), and their possible combinations, must be evaluated. This day may not be far off; a review of ongoing studies at clinicaltrials.gov reveals multiple candidate drugs under evaluation. For now, neurologists should keep a lumbar puncture tray handy, but they needn't stock up.

Alzheimer's CSF Test: Useful or Useless?: Does It Matter?

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Medscape Today

Andrew Wilner, MD

The second question, is does any additional diagnostic accuracy provided by the CSF test matter? In clinical practice, a laboratory test that confirmed Alzheimer's disease would remove ambiguity in early cases and limit consideration of other disorders that may present with symptoms suggestive of Alzheimer's dementia such as Creutzfeldt-Jakob disease, frontotemporal dementia, normal pressure hydrocephalus, Parkinson's disease with Lewy body dementia, vascular dementia, and depression. In some of these diseases, prompt diagnosis could lead to earlier effective treatment, such as shunting for normal pressure hydrocephalus or antidepressive medications for depression.

The truly persuasive argument for CSF testing in clinical practice would be the reality of a disease-modifying therapy that prevents or slows the progression of Alzheimer's disease. However, not only is there no "magic bullet" for the prevention of Alzheimer's disease, there is no bullet at all.[4] The current treatments offer modest, temporary, and symptomatic improvement at best. For most patients with mild cognitive deficits concerned about the development of Alzheimer's disease, a careful history, physical, and neurological evaluation with close clinical follow-up (a "wait and see" approach) is practical and appears cost effective.

Once people become demented, they can no longer plan for their financial future or dictate their end-of-life care. An early diagnosis of Alzheimer's disease, rather than late, permits a person more autonomy in directing his or her future. However, an early diagnosis of Alzheimer's disease may have negative psychological consequences in an otherwise well-functioning person who must now consider an inexorable decline towards a state of personal oblivion. Consequently, the pros and cons of early diagnosis must be carefully weighed in each individual prior to such a confirmatory test.

The success of clinical trials requires not only that the treatment be effective, but that all subjects have the disease in question. Subjects who have other diseases contaminate the sample and confound results. To improve the likelihood of successful clinical trials for Alzheimer's disease, potential subjects should be considered for CSF and other diagnostic testing. Revision of research criteria for the diagnosis of Alzheimer's disease that includes abnormal biomarkers has been proposed.[5]

Current Indications for CSF Testing
At present, CSF and other biomarker Alzheimer's testing should be reserved for patients who present a diagnostic dilemma, patients with suspected dementia for whom a diagnosis of probable Alzheimer's disease would provide more solace than worry, and patients entering clinical trials.

Alzheimer's CSF Test: Useful or Useless?:

Alzheimer's disease

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Medscape Today

Andrew Wilner, MD

According to a recent editorial, neurologists should be sharpening their lumbar puncture needles in order to obtain cerebrospinal fluid (CSF) to improve their diagnostic accuracy of Alzheimer's disease.[1] The CSF test employs a 2-component mixture model of beta-amyloid 1-42 (AB1-42) and phosphorylated tau protein 181 (P-tau 181P).[2] Model building and validation relied on data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). The sensitivity of the test was 90% in those with Alzheimer's disease, 72% in those with mild cognitive impairment (MCI), and 36% in controls. The specificity was only 62%.

Commercial assays to diagnose Alzheimer's disease by measurement of CSF beta-amyloid and tau protein have been available for more than a decade. Despite more than 5 million Americans with Alzheimer's disease, and millions more at risk, these CSF tests have yet to be widely adopted by clinical neurologists. At a minimum, there are 2 crucial questions that must be answered before recommending CSF examination as a routine test for Alzheimer's disease.

The first question is does CSF examination improve the accuracy of clinical diagnosis? Clinical diagnostic accuracy of probable Alzheimer's disease according to the standard National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria using autopsy as confirmation produces greater than 85% accuracy.[3] It is not clear how much additional precision is added by a positive CSF test in patients with clinically evident Alzheimer's disease. However, CSF testing may allow more accurate earlier diagnosis.