Introduction:

When you have lost the majority of your own hair, the presence of someone else’s hair in one of your socks, a hair that has somehow draped itself mid-length between two of your toes, can be a minor but enduring annoyance at the back of one’s awareness.  In a similar manner, odd pieces of information that one comes across in reading incessantly, can produce a similar annoyance, drifting in and out of one’s awareness, quietly nagging as one tries to go about one’s work.  Finding an opportune moment during the day to pull off one’s shoe and sock and remove that offending hair often must be put off until a moment when no one is watching.  The same thing can be said for finding time to deal with those nagging bits of information.

Back in June, Nathan Seppa wrote a short review in Science News, about an even shorter report published in the May issue of the Journal of the American Geriatrics Society.  The report tells us that spouses who care for partners suffering from dementia are at six times greater risk of eventually suffering from dementia themselves.    The article has not been listed on PubMed yet but you can download a free copy at the journal’s website:

http://www3.interscience.wiley.com/cgi-bin/fulltext/123421692/PDFSTART

The data analyzed that led researchers to this conclusion comes from what is usually called the Cache County Study on Memory Health and Aging. This is a collaborative study between three Universities, Johns Hopkins, Duke and Utah State.  Data has been collected and is being analyzed seeking genetic and environmental factors correlated with Alzheimer’s disease or dementia.  The study started in 1995 and enrolled 5,092 people, which is 90% of the people who live in Cache County, Utah.  Of these participants, 800 are over 85 years old.  Cache County residents are not average;  people live longer, are better educated, have less chronic disease than comparable populations elsewhere.

There were 1,221 married couples in which both partners were older than 65 enrolled at the start of the study. Over 900 people developed dementia during the study. Of the 2,442 married people, 225 were diagnosed with dementia.  If one member of a couple was diagnosed with dementia, their spouse was six times as likely to develop dementia compared to those with spouses without dementia.

The researchers theorize that the chronic stress of caring for a spouse with dementia might explain this increased risk.

What’s been nagging me is whether stress is an adequate explanation for this greater risk?  What do we know of risk of dementia for people under other stressful conditions?

A June 2010 paper published in the Archives of General Psychiatry reported on the association of post-traumatic stress disorder (PTSD) in military veterans and risk for developing dementia. The risk of those with PTSD increased by approximately 77%.  Rounding that number up, we could say that PTSD doubled risk for dementia.

Is attending a sick spouse a more significant stress than having PTSD?  But is the stress of care giving enough  but to cause triple the risk, of PTSD?

A study conducted in California, published this June in the Journal of the American College of Cardiology, provides more information on those caring for spouses with dementia. This study followed 78 older people, 55 of whom were caregivers for spouses with Alzheimer’s disease and the remaining 23 were living with healthy spouses not showing signs of dementia.  Those caring for spouses with dementia had worse endothelial function than those living with healthy spouses and the impact on endothelial function worsened with the severity of the Alzheimer’s disease in their spouse.

The same research group reported in 2007 that spousal caregivers have elevated tissue plasminogen activator (t-PA) antigen compared to non-caregivers. 

The risk of having elevated blood pressure goes up significantly in caregivers as well.  The Hazard Ratio (HR) for caregivers compared to controls was 4.86 in a 1999 California study.    In other words the caregivers were almost five times more likely to have elevated blood pressure.

Caring for a spouse with Alzheimer’s also increases d-dimer levels suggesting higher levels of fibrin and clotting activity. 

A May 2010 paper, reported a Swiss study’s conclusion that caring for an ill spouse also increases blood hyper-coagulability.  This study looked at 108 people caring for spouses with Alzheimer’s disease. These caregivers were interviewed weekly and the difficulty of their week rated by ranking occurrence of problem behaviors by their spouse.  These behavior scores were compared to a pro-coagulant index calculated from various blood measurements.

Given these various studies, there is strong argument that caring for a demented spouse suffering from Alzheimer’s is bad for one’s health, leading to increased risk for cardiovascular disease and even risk for dementia.  Yet is the effect injurious enough to explain the six times increase seen in the Cache County Data?

There are several other possibilities that may add to this risk.

The couples in the Cache County data were married an average of 49 years at the start of the study.  During their lives together, they were likely exposed to nearly the same environmental factors that either increase or decrease risk of Alzheimer’s as their spouse was exposed to.

For example, their food choices were likely similar if not identical.  Regular readers will recall my obsession with the analysis of data from the Kame Project that suggests drinking juice protects against Alzheimer’s disease.   A 2006 report told us that the risk for developing Alzheimer’s disease dropped by 76% in those who drank juice three times per week compared to those who drank juice less than once a week.

What are the odds of both partners either being in the habit of drinking juice or not?

What if Alzheimer’s was due in part to a chronic infection?  It would be likely for both spouses to carry such an infection after so many years living together.

Over the years a number of researchers have considered it possible that Chlamydia pneumoniae infection in the brain is linked to development of Alzheimer’s disease.  The earliest paper attempting to link Alzheimer’s disease to C. pneumoniae infection appeared in 1987 but was unable to establish a link.    Yet the theory continues to pop up in the medical literature and some studies support the claims that infection with Chlamydia pneumonia increases risk for Alzheimer’s disease.

In 1998, post mortem examinations of the brains of people who suffered from Alzheimer’s disease found a far higher frequency of infection by C. pneumonia than in controls. Using polymerase chain reaction (PCR) assays to test parts of the brain with Alzheimer disease pathology, these researchers found C. pneumoniae DNA sequences in 17 of 19 Alzheimer’s brains.  Only 1 of 19 control brains tested positive.  While some researchers have found signs of infection, others have not. 

In 2002 a Danish group reported they had failed to identify any increase in C. pneumoniae antibodies in people with Alzheimer’s or heart disease.     A 2006 Greek paper did find an association between C. Pneumoniae antibodies and carotid plaque formation. Canadian doctors tried giving Alzheimer’s patients long term doses of antibiotics and reported their results in 2004.  Although they could find no evidence that C. pneumoniae infections were more common in Alzheimer’s patients, those treated with antibiotics did do better on various measures of disease progression and disability.

This theory is far from accepted, but the possibility that both spouses in the Cache County and other caregiver studies were both exposed to similar infections and that the long term consequences of these infections could increase the risk for both to eventually develop Alzheimer’s disease has not been ruled out with certainty.

It is more logical to assume that stress is only a partial explanation to the increased risk of dementia among caregivers but not a complete explanation.

Whatever the answer to this question turns out to be, the recent analysis of the Utah data, certainly should put all practitioners on alert.   Caretaking a spouse with Alzheimer’s disease has become a significant disease risk factor, especially for developing dementia.  Individuals in this category should be identified and singled out for exceptional care.

Obviously a renewed focus on stress reduction should be encouraged as this is the current working theory to explain the phenomenon.  From a complementary point of view, diet, exercise and sleep must also be emphasized, both to reduce stress and to reduce other risk factors associated with this disease.

We’ve reviewed many of these factors in earlier newsletters.  As a quick reminder for those who forget things easily, the current focus on nutritional prevention is focused on supplementation with liposomal curcumin extracts, fish oil and alpha-lipoic acid.  Obviously the effects seen in the Kame Project data can’t be ignored and daily juice intake should also be encouraged.  Whether or not high dose antibiotics should be tried to treat potential C. pneumoniae infections is still under debate.

Greater Risk of Dementia When Spouse Has Dementia? The Cache County Study : [See editorial comments by Dr. Peter P. Vitaliano, pp 976–978] (p 895-900)
Maria C. Norton, Ken R. Smith, Truls Østbye, JoAnn T. Tschanz, Chris Corcoran, Sarah Schwartz, Kathleen W. Piercy, Peter V. Rabins, David C. Steffens, Ingmar Skoog, John C. S. Breitner, Kathleen A. Welsh-Bohmer
Published Online: May 6 2010 10:15AM
DOI: 10.1111/j.1532-5415.2010.02806.x

Greater Risk of Dementia When Spouse Has Dementia? The Cache

County Study

[See editorial comments by Dr. Peter P. Vitaliano, pp 976–978]

Maria C. Norton, PhD,abc Ken R. Smith, PhD,de Truls Østbye, MD, PhD,fgh JoAnn T. Tschanz, PhD,bc

Chris Corcoran, ScD,ci Sarah Schwartz, MS,ci Kathleen W. Piercy, PhD,ac Peter V. Rabins, MD, MPH,j

David C. Steffens, MD,k Ingmar Skoog, MD, PhD,l John C. S. Breitner, MD, MPH,mn Kathleen A.

Welsh-Bohmer, PhD,g for the Cache County Investigators

OBJECTIVES: To examine the effects of caring for a spouse

with dementia on the caregiver’s risk for incident dementia.

DESIGN: Population-based study of incident dementia in

spouses of persons with dementia.

SETTING: Rural county in northern Utah.

PARTICIPANTS: Two thousand four hundred forty-two subjects (1,221 married couples) aged 65 and older.

MEASUREMENTS: Incident dementia was diagnosed in 255 subjects, with onset defined as age when subject met Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, criteria for dementia. Cox proportional hazards regression tested the effect of time-dependent exposure to dementia in one’s spouse, adjusted for potential confounders.

RESULTS: A subject whose spouse experienced incident dementia onset had a six times greater risk for incident dementia as subjects whose spouses were dementia free (hazard rate ratio (HRR)56.0, 95% confidence interval (CI)52.2–16.2, Po.001). In sex-specific analyses, husbands had higher risks

(HRR511.9, 95% CI51.7–85.5, P5.01) than wives (HRR53.7, 95% CI51.2–11.6, P5.03).

CONCLUSION: The chronic and often severe stress associated with dementia caregiving may exert substantial risk for the development of dementia in spouse caregivers. Additional (not mutually exclusive) explanations for findings are discussed. J Am Geriatr Soc 58:895–900, 2010.

Norton MC, Smith KR, Østbye T, Tschanz JT, Corcoran C, Schwartz S, et al. Greater Risk of Dementia When Spouse Has Dementia? The Cache County Study. J Am Soc Ger. May, 2010 (p 895-900)

Yaffe K, Vittinghoff E, Lindquist K, Barnes D, Covinsky KE, Neylan T, et al. Posttraumatic stress disorder and risk of dementia among US veterans. Arch Gen Psychiatry. 2010 Jun;67(6):608-13.

Mausbach BT, Roepke SK, Ziegler MG, Milic M, von Känel R, Dimsdale JE, et al. Association between chronic caregiving stress and impaired endothelial function in the elderly. J Am Coll Cardiol. 2010 Jun 8;55(23):2599-606.

Mausbach BT, von Känel R, Aschbacher K, Roepke SK, Dimsdale JE, Ziegler MG, Mills PJ, et al. Spousal caregivers of patients with Alzheimer’s disease show longitudinal increases in plasma level of tissue-type plasminogen activator antigen.

Psychosom Med. 2007 Nov;69(8):816-22.

Shaw WS, Patterson TL, Ziegler MG, Dimsdale JE, Semple SJ, Grant I. Accelerated risk of hypertensive blood pressure recordings among Alzheimer caregivers. J Psychosom Res. 1999 Mar;46(3):215-27.

von Kanel R, Dimsdale JE, Adler KA, Patterson TL, Mills PJ, Grant I. et al. Exaggerated plasma fibrin formation (D-dimer) in elderly Alzheimer caregivers as compared to noncaregiving controls. Gerontology. 2005 Jan-Feb;51(1):7-13.

von Känel R, Mausbach BT, Dimsdale JE, Mills PJ, Patterson TL, Ancoli-Israel S, et al. Problem Behavior of Dementia Patients Predicts Low-Grade Hypercoagulability in Spousal Caregivers. Gerontol A Biol Sci Med Sci. 2010 May 19.

Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB. Fruit and vegetable juices and Alzheimer’s disease: the Kame Project.  Am J Med. 2006 Sep;119(9):751-9.

Renvoize EB, Awad IO, Hambling MH. A sero-epidemiological study of conventional infectious agents in Alzheimer’s disease. Age Ageing. 1987 Sep;16(5):311-4.

Med Microbiol Immunol. 1998 Jun;187(1):23-42.

Identification and localization of Chlamydia pneumoniae in the Alzheimer’s brain.

Balin BJ, Gérard HC, Arking EJ, Appelt DM, Branigan PJ, Abrams JT, Whittum-Hudson JA, Hudson AP.

Department of Pathology and Laboratory Medicine, MCP-Hahnemann School of Medicine, Allegheny University of the Health Sciences, Philadelphia, PA 19102, USA.

Abstract

We assessed whether the intracellular bacterium Chlamydia pneumoniae was present in post-mortem brain samples from patients with and without late-onset Alzheimer’s disease (AD), since some indirect evidence seems to suggest that infection with the organism might be associated with the disease. Nucleic acids prepared from those samples were screened by polymerase chain reaction (PCR) assay for DNA sequences from the bacterium, and such analyses showed that brain areas with typical AD-related neuropathology were positive for the organism in 17/19 AD patients. Similar analyses of identical brain areas of 18/19 control patients were PCR-negative. Electron- and immunoelectron-microscopic studies of tissues from affected AD brain regions identified chlamydial elementary and reticulate bodies, but similar examinations of non-AD brains were negative for the bacterium. Culture studies of a subset of affected AD brain tissues for C. pneumoniae were strongly positive, while identically performed analyses of non-AD brain tissues were negative. Reverse transcription (RT)-PCR assays using RNA from affected areas of AD brains confirmed that transcripts from two important C. pneumoniae genes were present in those samples but not in controls. Immunohistochemical examination of AD brains, but not those of controls, identified C. pneumoniae within pericytes, microglia, and astroglia. Further immunolabelling studies confirmed the organisms’ intracellular presence primarily in areas of neuropathology in the AD brain. Thus, C. pneumoniae is present, viable, and transcriptionally active in areas of neuropathology in the AD brain, possibly suggesting that infection with the organism is a risk factor for late-onset AD.

PMID: 9749980 [PubMed – indexed for MEDLINE]

Nochlin D, Shaw CM, Campbell LA, Kuo CC. Failure to detect Chlamydia pneumoniae in brain tissues of Alzheimer’s disease. Neurology. 1999 Nov 10;53(8):1888.

Bruunsgaard H, Østergaard L, Andersen-Ranberg K, Jeune B, Pedersen BK. Proinflammatory cytokines, antibodies to Chlamydia pneumoniae and age-associated diseases in Danish centenarians: is there a link?  Scand J Infect Dis. 2002;34(7):493-9.

Kaperonis EA, Liapis CD, Kakisis JD, Perrea D, Kostakis AG, Karayannakos PE. The association of carotid plaque inflammation and Chlamydia pneumoniae infection with cerebrovascular symptomatology. J Vasc Surg. 2006 Dec;44(6):1198-204.

Loeb MB, Molloy DW, Smieja M, Standish T, Goldsmith CH, Mahony J, et al. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease.  J Am Geriatr Soc. 2004 Mar;52(3):381-7.

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