Survival of Outpatients with Alzheimer-type Dementia John S. Walsh, BS; H. Gilbert Welch, MD, MPH; and Eric B. Larson, MD, MPH
Objective: To study the clinical course of Alzheimer-type dementia and those factors that might predict or influence the length of survival. Design: A prospective cohort study. Participants: One hundred and twenty-six patients diagnosed with Alzheimer-type dementia were selected from among 200 consecutive outpatients evaluated for suspected dementia from 1980 to 1982. All 126 patients had at least 6 years of follow-up. Setting: All patients were initially seen as outpatients at a university hospital. Measurements and Main Results: Survival analysis was done using Kaplan-Meier estimates and the Cox proportional hazards model. The mean age at symptom onset was 73.9 years and at enrollment in the study, 77.6 years. The median survival from time of enrollment in the study was 5.3 years (range, 0.2 to 7.2+ years) and from symptom onset, 9.3 years (range, 1.8 to 16+ years). Dementia severity, as measured by the Mini-Mental State Examination (MMSE), was strongly associated with survival (P < 0.001); the median survival of patients with scores of 18 or below was 3 years less than that of patients with scores above 18 (relative risk, 2.7; 95% CI, 1.6 to 4.4). Comorbid conditions and symptom duration were not related to survival. A multivariate analysis of age at symptom onset and of historical features showed that the combination of wandering and falling (relative risk, 2.1; 95% CI, 0.9 to 5.2) and the presence of behavioral problems (relative risk, 1.4; 95% CI, 0.7 to 2.9) at the time of evaluation appeared to adversely affect survival. Conclusions: Length of survival in patients with Alzheimer-type dementia is highly variable; severity of disease (not duration), the combination of wandering and falling, and behavioral problems are associated with shorter survival. Our findings, if confirmed, may provide prognostic information for families and professionals and suggest areas in which interventions to improve survival might be focused.
Alzheimer-type dementia is a major health problem that is destined to grow. It is estimated to afflict approximately 2 million Americans (1) and is probably the fourth leading cause of death among the elderly (2). Recent evidence suggests that the prevalence of Alzheimer-type dementia may be extremely high among the very old, approaching 50% in persons over 85 years of age (3). Clearly, the prevalence of Alzheimer-type dementia and the number of deaths for which it is responsible will rise considerably as the U.S. population ages. At present, the progressive course of Alzheimer-type dementia cannot be reversed. Thus, until effective treatment is available, identification and amelioration of associated conditions that shorten survival may prove to be the best strategy for lessening the burden of the disease. The development of such strategies requires data on mortality in patients with Alzheimer-type dementia and on factors that influence prognosis. Prognostic information is important because it enables clinicians to help patients and families for the future. The mean survival in patients with Alzheimer-type dementia has been shown to range from 5 to 8 years (4-8); however, studies of factors that might affect survival are limited (9, 10). Data from prospective cohort studies could provide clinicians with prognostic information for patients with Alzheimer-type dementia and their families and may suggest intervention strategies for improving the morbidity and mortality in Alzheimer-type dementia. Our study examined survival and analyzed factors possibly associated with survival in patients with Alzheimer-type dementia. The study included consecutive outpatients presenting with complaints of dementia who, after a thorough and systematic investigation, were diagnosed with Alzheimer-type dementia. Clinical data on all patients were recorded at intake, and all patients were followed for at least 6 years. Methods Patient Population
Annals of Internal Medicine. 1990;113:429-434. From the University of Washington and Seattle Veterans Affairs Medical Center, Seattle, Washington. For current author addresses, see end of text.
Subjects for our study were selected from among 200 patients evaluated for symptoms of cognitive impairment. The subjects were consecutively enrolled as outpatients and nearly all (98%) were referred from the Geriatrics and Family Services Program, Department of Psychiatry, University of Washington. All patients met four entry criteria: an age greater than 60 years; suspected global cognitive impairment based on symptoms (reported by patient or family) such as forgetfulness, confusion, inability to care for self, and slow thought process; symptoms of cognitive impairment of at least 3 months duration; and a willingness to undergo diagnostic evaluation and to participate in follow-up for at least 1 year after evaluation. The patients, all of whom were enrolled in the study between 1980 and 1982, have been described previously in more detail (11). Only patients diagnosed with Alzheimer-type dementia were included in the study. Diagnoses for the 200 enrolled patients were established by a consensus group, which included the internist who evaluated the patient, a psychiatrist, a psychol© 1990 American College of Physicians
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ogist, a neuropathologist or neurologist, and the research nurses who coordinated the evaluation and follow-up of study patients. Diagnostic guidelines used by the consensus group were based on the research diagnostic criteria in use between 1980 and 1982—those suggested by Eisdorfer and Cohen (12) and the DSM-III criteria (13). The DSM-III criteria include loss of global cognitive function to a level that compromises the patient's ability to adapt to the environment, progressive deterioration, duration of symptoms of cognitive impairment of at least 6 months, and the absence of other causes of dementia. Only patients who, according to the consensus group, met the criteria for Alzheimer-type dementia and for whom Alzheimer-type dementia was the primary diagnosis were included in the study (n = 126). Pathologic findings associated with Alzheimer disease (large numbers of neurofibrillary tangles and senile plaques [14]) have confirmed the diagnosis in 24 of 25 patients who had an autopsy. The clinical courses of the 52 patients who died but did not have an autopsy were consistent with Alzheimer-type dementia. Data Collection All patients had a standardized diagnostic evaluation including initial medical, psychiatric, diagnostic laboratory, and neuropsychological evaluations. A family member, friend, or caregiver acquainted with the patient accompanied the patient to provide and verify details of the patient's history. Historical data were gathered by the evaluating physician (EBL). Particular attention was paid to symptom duration; age at symptom onset; and concurrent medical, neurologic, psychological, and behavioral problems. All patients were evaluated and staged using two short, standardized rating examinations: the MiniMental State Examination (MMSE) (15) and the modified Blessed Dementia Rating Scale (mDRS) (16). The MMSE rates cognitive impairment on a 0 (worst) to 30 (best) point scale. The mDRS is a 17-point scale that includes sections evaluating habits and activities of daily living. For our analysis the mDRS was inverted so that it ranged from 0 (worst) to 17 (best) points. Our analysis used follow-up data collected on patients after study enrollment until either the death of the patient or 1 September 1988. These data contain information on the medical, psychological, and social status of the patient.
large portion of the disease course, but with a disease like Alzheimer-type dementia that typically has an insidious onset, symptom onset provides an imprecise starting point. Measuring survival from study entry has the advantage of using a discrete starting point. However, patients are in various stages of disease at this time. When analyzing survival in relation to characteristics present and determined at study entry, measuring survival from the date of study entry is clearly appropriate. However, when analyzing the relation of survival to historical features recorded at entry, but present beforehand, the choice is less clear. For these reasons, we have reported results of both analyses. Results Patient Population and Overall Survival Experience The mean age at symptom onset for the study patients was 73.9 years (CI, 72.6 to 75.2 years). The mean age at study entry when patients presented for evaluation was 77.6 years (CI, 76.4 to 78.8 years). Seventytwo percent of patients were female (n = 91). The mean symptom duration was 3.8 years (CI, 3.4 to 4.2 years) before study entry; the median symptom duration before entry was 3.0 years (range, 0.2 to 11 years). At the initial evaluation, only 3% of the patients lived in group or nursing homes (n = 4). As of 1 September 1988, 77 of the 126 patients had died. Survival curves from symptom onset and study entry are shown in Figure 1. The median survival from symptom onset was 9.3 years (range, 1.8 to 16+ years; first quartile, 6.1 years; third quartile, 10.3 years), whereas the median survival from study entry was 5.3 years (range, 0.2 to 7.2+ years; first quartile, 2.9 years; third quartile, 6.2 years). Age and Survival The relation between age and survival is complex.
Statistical Analysis Measures of mental functioning, certain historical findings, and laboratory results obtained at study entry were used to stratify the 126 patients into different subgroups. Because 49 of the 126 patients have not died, the Kaplan-Meier method (17) (survival estimation from incomplete observations) was used in the analysis. The survival patterns of different subgroups were compared using both the log-rank test and the proportional hazards linear model. Results are reported with P values for the log-rank comparisons, and relative risks and associated 95% confidence intervals (CIs) for the proportional hazards model. Table 1 shows the specific historical and laboratory variables that were examined for their relation to survival. Behavioral problems included suspiciousness or paranoia, agitation, incontinence, wandering, hallucination, or inattention to personal hygiene. The comorbid conditions that were considered included cardiac, respiratory, or neurologic disease, and cancer. A hearing problem was defined by a reported need for or use of a hearing aid. Prescription drugs included anti-psychotic, hypnotic-sedative, and antihypertensive agents. Age was controlled for using the Cox proportional hazards regression model (18). Survival Calculations Ideally, survival time is measured from disease onset to death. However, because disease onset in Alzheimer-type dementia is not a discrete event, one of two proxy starting points must be used: either the date when symptoms were first noted or the date when symptoms were severe enough to cause patients or families to seek medical attention. Each starting point has advantages and disadvantages. Measuring survival time from symptom onset has the advantage of including a 430
There was no relation between age at study entry and survival. However, patients more advanced in age at symptom onset had a shorter survival (P < 0.01, logTable 1. Historical and Examination for Their Relation with Survival Historical variables Age at study entry Age at symptom onset Alcohol use Behavioral problems Comorbid conditions Decrease in appetite Depression Hearing problems Previous fractures Restlessness Sex Symptom duration Use of prescription drugs Vision problems Wandering and falling Examination variables Dementia measures Dementia Rating Scale Mini-Mental State Examination Laboratory tests Hematocrit Serum creatinine Serum folate
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Variables
Tested
Figure 1. Survival curves for patients with Alzheimer-type dementia {n = 126). The left panel shows survival starting from symptom onset; the right panel shows survival starting from study entry. rank test). This apparent paradox is related to the finding that older patients had a shorter symptom duration. The mean symptom duration for patients more than 75 years of age was 10 months shorter than that for patients 75 years of age or less (CI, 0.2 to 1.6 years). In addition, older patients had a greater rate of decline before entry; that is, even though older patients had a shorter symptom duration than younger patients, their MMSE scores at study entry did not differ. Variables Tested for a Relation with Survival Of the variables hypothesized to have a relation with survival, dementia severity, the combination of wandering and falling, behavioral problems, one sensory impairment (hearing loss), and age at symptom onset were found to have a statistically significant relation. Other historical features including symptom duration, depression, restlessness, incontinence, fractures, comorbid conditions, vision impairment, loss of appetite, use of prescription drugs, and use of alcohol did not have a significant relation with survival. Anemia (hematocrit < 0.36), poor nutritional status (serum folate level < 9 nmol/L), and renal dysfunction (serum creatinine > 97 jLtmol/L), were not associated with poor survival. Patients with more severe dementia at entry had a poorer prognosis. At study entry, the median MMSE score was 18 (range, 0 to 30) and the median mDRS score was 4.5 (range, 0 to 15.5). The median survival time from study entry for patients who scored 18 or below on the MMSE was 4.3 years, whereas patients scoring higher than 18 had a median survival of 7.2 years (P < 0.0001, log-rank test). The relative risk for death in patients with low MMSE scores was 2.7 (CI, 1.6 to 4.4). Table 2 shows survival for patients grouped into quartiles based on MMSE scores. Each of these four groups of patients had a significantly different survival time (P < 0.01); groups with lower MMSE scores
had a shorter survival than groups with higher scores. Similarly, patients scoring lower than 4.5 on the mDRS had a median survival of 4.5 years, whereas patients scoring 4.5 or more had a median survival of 7.0 years (P < 0.01). Controlling for age did not change the level of statistical significance. Table 3 shows the three historical features whose relation to survival was significant (P < 0.05, log-rank test). Patients who presented with a history of wandering and falling had a significantly shorter survival time than did patients who neither wandered nor fell before entry (Figure 2). The relative risk for death in patients with a history of wandering and falling was 3.1 (CI, 1.4 to 6.6). The presence of any of the six behavioral problems assessed at entry (history of suspiciousness or paranoia, agitation, incontinence, wandering, hallucinations, or inattention to personal hygiene) also portended a poorer prognosis (relative risk, 1.5; CI, 1.0 to 2.5). Patients with a hearing impairment had a shorter survival time than did patients without an impairment (relative risk, 1.5; CI, 0.9 to 2.5). Except for hearing loss, controlling for age did not change the significance of these associations. A multivariate model predicting survival using age at symptom onset and the above three historical features
Table 2. Patient Survival Stratified by Initial Mental State Examination (MMSE) Score Quartile
MMSE Score
Median Survival from Entry (Range) y
First Second Third Fourth
< 13 13-18 19-23 >23
3.4 4.5 6.8 7.2
(0.2-7 +) (0.8-7 +) (0.6-7.2 +) (0.8-7.2 +)
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Table 3. Univariate acteristics at Study Characteristic
Wandering and falling Yes No Behavioral problems Yes No Hearing problems Yes No
Analysis of Relation between Entry and Survival
Patients
Median Median Survival Survival from from Entry Symptom Onset
n
y
Char-
Relative Risk (95% CI)
10 64
3.0 6.2
5.4 9.3*
3.1 (1.4 to 6.6)
66 56
4.3 6.0t
8.9 10.3t
1.5 (1.0 to 2.5)
31 94
4.0 5.3t
7.6 9.6t
1.5 (0.9 to 2.5)
* P < 0.005. t P < 0.05. The P values express the probability that the observed difference in median survival between patients with and without the characteristic occurred by chance, using the log-rank test.
was investigated. The combination of wandering and falling (relative risk, 2.1; CI, 0.9 to 5.2) and behavioral problems (relative risk, 1.4; CI, 0.7 to 2.9) at the time of evaluation appeared to have an independent effect on survival. After controlling for age and the other historical features, hearing impairment (a feature known to correlate with increasing age [19]) had no independent effect on survival. Discussion The survival of patients with Alzheimer-type dementia is highly variable. The length of survival from symptom onset in our cohort ranged from 1.8 to at least 16 years. Our study found that later age of onset, dementia severity, the combination of wandering and falling, behavioral problems, and possibly hearing problems were associated with shorter survival. Factors found not to influence survival were symptom duration, sex, depression, restlessness, comorbid conditions, vision problems, a reported decrease in appetite, the use of prescription drugs, and selected laboratory abnormalities (anemia, a serum folate level < 9 nmol/L, and an abnormal serum creatinine level). For 50% of our patients, survival from symptom onset was more than 9 years. The survival in this cohort is longer than other investigators have reported in part because of the different starting points used for calculating survival (symptom onset as opposed to study entry). The three studies measuring survival from study entry found a median survival of 3.4, 3.5, and 5.7 years, respectively (4, 6, 8), whereas those measuring survival from the onset of symptoms found a median survival of 7 and 8.1 years, respectively (5-7). Further, because this cohort was selected from outpatients, most of whom were having their first evaluation for dementia, our patients were probably less severely ill than those participating in previous studies. Reports on the association of age and survival have 432
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been inconsistent. Both Molsa and colleagues (8) and Barclay and associates (6) measured survival from study entry. The former group found no relation between age and survival and the latter reported that younger subjects had shorter survival time. Two studies that measured survival from symptom onset found that a later age of onset adversely affects survival (7, 20). Our study also found that a later age of onset adversely affects survival when measured from age at symptom onset, but that no relation exists when measured from study entry. This apparent discrepancy may be explained by the shorter symptom duration of older patients before presentation. This study confirms the report by Kaszniak and colleagues (10) that severity of illness, as measured by screening neuropsychologic tests, has a strong relation with survival. Brief, easily administered tests like the MMSE or mDRS correlate well with more detailed, prolonged neuropsychologic tests and can provide useful prognostic information. The combination of wandering and falling adversely affected survival in our cohort. The difference in median years of survival between patients who wandered and fell and patients who neither wandered nor fell was more than 3 years. This finding is not surprising. Patients with Alzheimer-type dementia are known to be at a considerable risk for falls and fractures compared with nondemented persons of the same age (21). Fractures tend to immobilize patients and place them at risk for other potentially lethal events (for example, pulmonary embolus and aspiration pneumonia). Consequently, effective strategies to control wandering and prevent falling in patients with Alzheimer-type dementia might help reduce morbidity and improve survival. As Barclay and colleagues (9) have also reported, the presence of behavioral problems portends a worse prognosis. Although the presence and number of such prob-
Figure 2. Survival curves for patients with Alzheimer-type dementia who had a history of wandering and falling (n = 10, broken line) compared with patients with Alzheimer-type dementia who had no history of wandering or falling (n = 64, solid line).
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lems have been linked to worsening dementia (22), existing data do not explain how behavioral problems adversely effect outcome. The multivariate analysis suggests that behavioral problems are related to wandering and falling but are not as important in predicting survival. On the other hand, behavioral problems themselves and the treatment applied to control them may be responsible for poor outcomes. Sedative and hypnotic drugs used to treat agitation, for example, have been associated with falling and hip fractures (23). We believe the management of behavioral problems needs further study, including studies of interventions designed to effectively and safely ameliorate these difficult and frequently frustrating problems. Although hearing impairment has also been linked to cognitive decline in patients with Alzheimer-type dementia (24, 25), its relation with survival is unclear. The presence of hearing problems did portend a worse prognosis in our cohort. Although controlling for age reduced the statistical significance of the relation (P = 0.20), this finding does not mean that no association exists between hearing problems and survival. Research (including therapeutic trials) focused on the relation between hearing loss and survival could clarify the importance of the association. Some features found not to have an association with survival deserve comment. The fact that symptom duration, for example, had no bearing on survival, suggests that substantial heterogeneity exists among patients with Alzheimer-type dementia. Some of this heterogeneity probably relates to the disease. Patients with long symptom duration before evaluation did not die sooner than patients with short symptom duration. Host factors also probably play a role in Alzheimer-type dementia heterogeneity. Although the presence of comorbid conditions and use of prescription drugs did not affect survival, the relatively small sample (especially the size of subgroups) and the measures used in our study may not have been powerful enough to detect a difference. On the other hand, age at symptom onset did affect survival suggesting that vigor and other host factors associated with age are important determinants of outcome. Our study had two main limitations. First, because this was a preliminary investigation, many variables were tested for a relation with survival. This strategy allows for the chance appearance of a significant finding simply because many were tested. However, most of the associations are logical and are supported by existing data. In addition, we did limit our analysis to variables selected a priori before analysis from a larger list of variables. Second, because the actual cause of death was not investigated, inferences from our results must be tempered. There is no information with regard to the direct causal role of those characteristics we found to be related to survival. Thus, it is entirely possible, for example, that wandering and falling serves as a marker for some other risk factor and that preventing falls would have no effect on mortality. Results from our study should provide useful information about the clinical course of Alzheimer-type dementia. For physicians, patients, and their families, measures of severity, like the MMSE, do provide accu-
rate prognostic information. For caregivers, the results support the common sense notion that efforts should be made to prevent or minimize falling. We hope our findings will stimulate other investigators to determine whether these results are generalizable to other populations. Acknowledgments: The authors thank Burton Reifler, MD; Shuzo M. Sumi, MD; and Suzanne Woo, PhD, for helping to collect the cohort; Connie Canfield, RN; Nina Chinn, RN; and Pam McLean, RN, for following the patients; and Jim Hughes, MS, and Duane Beekly for assisting with data analysis. The authors also thank the patients and their families for their participation and cooperation. Grant Support: In part by grants from the National Institute on Aging (AG05136; AG06781)—Alzheimer Disease Research Center, and the Alzheimer Disease Patient Registry. Requests for Reprints: Eric B. Larson, MD, MPH, Medical Director's Office, RD-30, University of Washington, Seattle, WA 98195. Current Author Addresses: Dr. Welch: Dartmouth-Hitchcock Medical Center, Center for Evaluative Clinical Sciences, Department of Community and Family Medicine, Hanover, NH 03756. Mr. Walsh: Department of Medicine, University of Washington, Seattle, WA 98195. Dr. Larson: Medical Director's Office, RD-30, University of Washington, Seattle, WA 98195.
References 1. Katzman R. Medical progress—Alzheimer's disease. N Engl J Med. 1986;314:964-73. 2. Katzman R. Editorial: the prevalence and malignancy of Alzheimer's disease. A major killer. Arch Neurol. 1976;33:217-8. 3. Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. JAMA. 1989;262:2551-6. 4. Schoenberg BS, Kokmen £ , Okazaki H. Alzheimer's disease and other dementing illnesses in a defined United States population: incidence rates and clinical features. Ann Neurol. 1987;22:724-9. 5. Reding MJ, Haycox J, Wigforss K, Brush D, Blass JP. Follow-up of patients referred to a dementia service. J Am Geriatr Soc. 1984;32: 265-8. 6. Barclay LL, Zemcov A, Blass JP, Sansone J. Survival in Alzheimer's disease and vascular dementias. Neurology. 1985;35:834-40. 7. Treves T, Korczyn AD, Zilber N, et al. Presenile dementia in Israel. Arch Neurol. 1986;43:26-9. 8. Molsa PK, Marttila RJ, Rinne UK. Survival and cause of death in Alzheimer's disease and multi-infarct dementia. Acta Neurol Scand. 1986;74:103-7. 9. Barclay LL, Zemcov A, Blass JP, McDowell FH. Factors associated with duration of survival in Alzheimer's disease. Biol Psychiatry. 1985;20:86-93. 10. Kaszniak AW, Fox J, Gandell DL, Garron DC, Huckman MS, Ramsey RG. Predictors of mortality in presenile and senile dementia. Ann Neurol. 1978;3:246-52. 11. Larson EB, Reifler BV, Sumi SM, Canfield CG, Chinn NM. Diagnostic evaluation of 200 elderly outpatients with suspected dementia. / Gerontol. 1985;40:536-43. 12. Eisdorfer C, Cohen D. Diagnostic criteria for primary neuronal degeneration of Alzheimer's type. J Fam Pract. 1980;4:553-7. 13. American Psychiatric Association Task Force. Task Force on Nomenclature and Statistics: Diagnostic and Statistical Manual of Mental Disorders. 3d edition. Washington DC: American Psychiatric Association; 1980. 14. Davis K, Katzman R. Senile dementia of the Alzheimer's type: defining a disease. In: Terry RD, Katzman R, eds. Neurology of Aging. Philadelphia: Davis; 1983. 15. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state." A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-98. 16. Blessed G, Tomlinson BE, Roth M. The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry. 1968;114:797-811. 17. Kaplan EL, Meier P. Non-parametric estimations from incomplete observations. / Am Stat Assoc. 1958;53:457-81. 18. Armitage P, Berry G. Statistical Methods in Modern Research. 2d edition. Oxford: Blackwell Scientific Publications; 1987:436.
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19. Milne JS. A longitudinal study of hearing loss in older people. Br J Audiol. 1977;11:7-14. 20. Sayetta RB. Rates of senile dementia, Alzheimer's type, in the Baltimore longitudinal study. J Chron Dis. 1986;39:271-86. 21. Buchner DM, Larson EB. Falls and fractures in patients with Alzheimer-type dementia. JAMA. 1987;257:1492-5. 22. Teri L, Larson EB, Reifler BV. Behavioral disturbance in dementia of the Alzheimer's type. J Am Geriatr Soc. 1988;36:1-6. 23. Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ. Psycho-
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tropic drug use and the risk of hip fracture. N Engl J Med. 1987; 316:363-9. 24. Uhlmann RF, Larson EB, Koepsell TD. Hearing impairment and cognitive decline in senile dementia of the Alzheimer's type. J Am Geriatr Soc. 1986;34:207-10. 25. Uhlmann RF, Larson EB, Rees TS, Koepsell TD, Duckert LG. Relationship of hearing impairment to dementia and cognitive dysfunction in older adults. JAMA. 1989;261:1916-9.
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Objective: To study the clinical course of Alzheimer-type dementia and those factors that might predict or influence the length of survival. Design: A prospective cohort study. Participants: One hundred and twenty-six patients diagnosed with Alzheimer-type dementia were selected from among 200 consecutive outpatients evaluated for suspected dementia from 1980 to 1982. All 126 patients had at least 6 years of follow-up. Setting: All patients were initially seen as outpatients at a university hospital. Measurements and Main Results: Survival analysis was done using Kaplan-Meier estimates and the Cox proportional hazards model. The mean age at symptom onset was 73.9 years and at enrollment in the study, 77.6 years. The median survival from time of enrollment in the study was 5.3 years (range, 0.2 to 7.2+ years) and from symptom onset, 9.3 years (range, 1.8 to 16+ years). Dementia severity, as measured by the Mini-Mental State Examination (MMSE), was strongly associated with survival (P < 0.001); the median survival of patients with scores of 18 or below was 3 years less than that of patients with scores above 18 (relative risk, 2.7; 95% CI, 1.6 to 4.4). Comorbid conditions and symptom duration were not related to survival. A multivariate analysis of age at symptom onset and of historical features showed that the combination of wandering and falling (relative risk, 2.1; 95% CI, 0.9 to 5.2) and the presence of behavioral problems (relative risk, 1.4; 95% CI, 0.7 to 2.9) at the time of evaluation appeared to adversely affect survival. Conclusions: Length of survival in patients with Alzheimer-type dementia is highly variable; severity of disease (not duration), the combination of wandering and falling, and behavioral problems are associated with shorter survival. Our findings, if confirmed, may provide prognostic information for families and professionals and suggest areas in which interventions to improve survival might be focused.
Alzheimer-type dementia is a major health problem that is destined to grow. It is estimated to afflict approximately 2 million Americans (1) and is probably the fourth leading cause of death among the elderly (2). Recent evidence suggests that the prevalence of Alzheimer-type dementia may be extremely high among the very old, approaching 50% in persons over 85 years of age (3). Clearly, the prevalence of Alzheimer-type dementia and the number of deaths for which it is responsible will rise considerably as the U.S. population ages. At present, the progressive course of Alzheimer-type dementia cannot be reversed. Thus, until effective treatment is available, identification and amelioration of associated conditions that shorten survival may prove to be the best strategy for lessening the burden of the disease. The development of such strategies requires data on mortality in patients with Alzheimer-type dementia and on factors that influence prognosis. Prognostic information is important because it enables clinicians to help patients and families for the future. The mean survival in patients with Alzheimer-type dementia has been shown to range from 5 to 8 years (4-8); however, studies of factors that might affect survival are limited (9, 10). Data from prospective cohort studies could provide clinicians with prognostic information for patients with Alzheimer-type dementia and their families and may suggest intervention strategies for improving the morbidity and mortality in Alzheimer-type dementia. Our study examined survival and analyzed factors possibly associated with survival in patients with Alzheimer-type dementia. The study included consecutive outpatients presenting with complaints of dementia who, after a thorough and systematic investigation, were diagnosed with Alzheimer-type dementia. Clinical data on all patients were recorded at intake, and all patients were followed for at least 6 years. Methods Patient Population
Annals of Internal Medicine. 1990;113:429-434. From the University of Washington and Seattle Veterans Affairs Medical Center, Seattle, Washington. For current author addresses, see end of text.
Subjects for our study were selected from among 200 patients evaluated for symptoms of cognitive impairment. The subjects were consecutively enrolled as outpatients and nearly all (98%) were referred from the Geriatrics and Family Services Program, Department of Psychiatry, University of Washington. All patients met four entry criteria: an age greater than 60 years; suspected global cognitive impairment based on symptoms (reported by patient or family) such as forgetfulness, confusion, inability to care for self, and slow thought process; symptoms of cognitive impairment of at least 3 months duration; and a willingness to undergo diagnostic evaluation and to participate in follow-up for at least 1 year after evaluation. The patients, all of whom were enrolled in the study between 1980 and 1982, have been described previously in more detail (11). Only patients diagnosed with Alzheimer-type dementia were included in the study. Diagnoses for the 200 enrolled patients were established by a consensus group, which included the internist who evaluated the patient, a psychiatrist, a psychol© 1990 American College of Physicians
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ogist, a neuropathologist or neurologist, and the research nurses who coordinated the evaluation and follow-up of study patients. Diagnostic guidelines used by the consensus group were based on the research diagnostic criteria in use between 1980 and 1982—those suggested by Eisdorfer and Cohen (12) and the DSM-III criteria (13). The DSM-III criteria include loss of global cognitive function to a level that compromises the patient's ability to adapt to the environment, progressive deterioration, duration of symptoms of cognitive impairment of at least 6 months, and the absence of other causes of dementia. Only patients who, according to the consensus group, met the criteria for Alzheimer-type dementia and for whom Alzheimer-type dementia was the primary diagnosis were included in the study (n = 126). Pathologic findings associated with Alzheimer disease (large numbers of neurofibrillary tangles and senile plaques [14]) have confirmed the diagnosis in 24 of 25 patients who had an autopsy. The clinical courses of the 52 patients who died but did not have an autopsy were consistent with Alzheimer-type dementia. Data Collection All patients had a standardized diagnostic evaluation including initial medical, psychiatric, diagnostic laboratory, and neuropsychological evaluations. A family member, friend, or caregiver acquainted with the patient accompanied the patient to provide and verify details of the patient's history. Historical data were gathered by the evaluating physician (EBL). Particular attention was paid to symptom duration; age at symptom onset; and concurrent medical, neurologic, psychological, and behavioral problems. All patients were evaluated and staged using two short, standardized rating examinations: the MiniMental State Examination (MMSE) (15) and the modified Blessed Dementia Rating Scale (mDRS) (16). The MMSE rates cognitive impairment on a 0 (worst) to 30 (best) point scale. The mDRS is a 17-point scale that includes sections evaluating habits and activities of daily living. For our analysis the mDRS was inverted so that it ranged from 0 (worst) to 17 (best) points. Our analysis used follow-up data collected on patients after study enrollment until either the death of the patient or 1 September 1988. These data contain information on the medical, psychological, and social status of the patient.
large portion of the disease course, but with a disease like Alzheimer-type dementia that typically has an insidious onset, symptom onset provides an imprecise starting point. Measuring survival from study entry has the advantage of using a discrete starting point. However, patients are in various stages of disease at this time. When analyzing survival in relation to characteristics present and determined at study entry, measuring survival from the date of study entry is clearly appropriate. However, when analyzing the relation of survival to historical features recorded at entry, but present beforehand, the choice is less clear. For these reasons, we have reported results of both analyses. Results Patient Population and Overall Survival Experience The mean age at symptom onset for the study patients was 73.9 years (CI, 72.6 to 75.2 years). The mean age at study entry when patients presented for evaluation was 77.6 years (CI, 76.4 to 78.8 years). Seventytwo percent of patients were female (n = 91). The mean symptom duration was 3.8 years (CI, 3.4 to 4.2 years) before study entry; the median symptom duration before entry was 3.0 years (range, 0.2 to 11 years). At the initial evaluation, only 3% of the patients lived in group or nursing homes (n = 4). As of 1 September 1988, 77 of the 126 patients had died. Survival curves from symptom onset and study entry are shown in Figure 1. The median survival from symptom onset was 9.3 years (range, 1.8 to 16+ years; first quartile, 6.1 years; third quartile, 10.3 years), whereas the median survival from study entry was 5.3 years (range, 0.2 to 7.2+ years; first quartile, 2.9 years; third quartile, 6.2 years). Age and Survival The relation between age and survival is complex.
Statistical Analysis Measures of mental functioning, certain historical findings, and laboratory results obtained at study entry were used to stratify the 126 patients into different subgroups. Because 49 of the 126 patients have not died, the Kaplan-Meier method (17) (survival estimation from incomplete observations) was used in the analysis. The survival patterns of different subgroups were compared using both the log-rank test and the proportional hazards linear model. Results are reported with P values for the log-rank comparisons, and relative risks and associated 95% confidence intervals (CIs) for the proportional hazards model. Table 1 shows the specific historical and laboratory variables that were examined for their relation to survival. Behavioral problems included suspiciousness or paranoia, agitation, incontinence, wandering, hallucination, or inattention to personal hygiene. The comorbid conditions that were considered included cardiac, respiratory, or neurologic disease, and cancer. A hearing problem was defined by a reported need for or use of a hearing aid. Prescription drugs included anti-psychotic, hypnotic-sedative, and antihypertensive agents. Age was controlled for using the Cox proportional hazards regression model (18). Survival Calculations Ideally, survival time is measured from disease onset to death. However, because disease onset in Alzheimer-type dementia is not a discrete event, one of two proxy starting points must be used: either the date when symptoms were first noted or the date when symptoms were severe enough to cause patients or families to seek medical attention. Each starting point has advantages and disadvantages. Measuring survival time from symptom onset has the advantage of including a 430
There was no relation between age at study entry and survival. However, patients more advanced in age at symptom onset had a shorter survival (P < 0.01, logTable 1. Historical and Examination for Their Relation with Survival Historical variables Age at study entry Age at symptom onset Alcohol use Behavioral problems Comorbid conditions Decrease in appetite Depression Hearing problems Previous fractures Restlessness Sex Symptom duration Use of prescription drugs Vision problems Wandering and falling Examination variables Dementia measures Dementia Rating Scale Mini-Mental State Examination Laboratory tests Hematocrit Serum creatinine Serum folate
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Variables
Tested
Figure 1. Survival curves for patients with Alzheimer-type dementia {n = 126). The left panel shows survival starting from symptom onset; the right panel shows survival starting from study entry. rank test). This apparent paradox is related to the finding that older patients had a shorter symptom duration. The mean symptom duration for patients more than 75 years of age was 10 months shorter than that for patients 75 years of age or less (CI, 0.2 to 1.6 years). In addition, older patients had a greater rate of decline before entry; that is, even though older patients had a shorter symptom duration than younger patients, their MMSE scores at study entry did not differ. Variables Tested for a Relation with Survival Of the variables hypothesized to have a relation with survival, dementia severity, the combination of wandering and falling, behavioral problems, one sensory impairment (hearing loss), and age at symptom onset were found to have a statistically significant relation. Other historical features including symptom duration, depression, restlessness, incontinence, fractures, comorbid conditions, vision impairment, loss of appetite, use of prescription drugs, and use of alcohol did not have a significant relation with survival. Anemia (hematocrit < 0.36), poor nutritional status (serum folate level < 9 nmol/L), and renal dysfunction (serum creatinine > 97 jLtmol/L), were not associated with poor survival. Patients with more severe dementia at entry had a poorer prognosis. At study entry, the median MMSE score was 18 (range, 0 to 30) and the median mDRS score was 4.5 (range, 0 to 15.5). The median survival time from study entry for patients who scored 18 or below on the MMSE was 4.3 years, whereas patients scoring higher than 18 had a median survival of 7.2 years (P < 0.0001, log-rank test). The relative risk for death in patients with low MMSE scores was 2.7 (CI, 1.6 to 4.4). Table 2 shows survival for patients grouped into quartiles based on MMSE scores. Each of these four groups of patients had a significantly different survival time (P < 0.01); groups with lower MMSE scores
had a shorter survival than groups with higher scores. Similarly, patients scoring lower than 4.5 on the mDRS had a median survival of 4.5 years, whereas patients scoring 4.5 or more had a median survival of 7.0 years (P < 0.01). Controlling for age did not change the level of statistical significance. Table 3 shows the three historical features whose relation to survival was significant (P < 0.05, log-rank test). Patients who presented with a history of wandering and falling had a significantly shorter survival time than did patients who neither wandered nor fell before entry (Figure 2). The relative risk for death in patients with a history of wandering and falling was 3.1 (CI, 1.4 to 6.6). The presence of any of the six behavioral problems assessed at entry (history of suspiciousness or paranoia, agitation, incontinence, wandering, hallucinations, or inattention to personal hygiene) also portended a poorer prognosis (relative risk, 1.5; CI, 1.0 to 2.5). Patients with a hearing impairment had a shorter survival time than did patients without an impairment (relative risk, 1.5; CI, 0.9 to 2.5). Except for hearing loss, controlling for age did not change the significance of these associations. A multivariate model predicting survival using age at symptom onset and the above three historical features
Table 2. Patient Survival Stratified by Initial Mental State Examination (MMSE) Score Quartile
MMSE Score
Median Survival from Entry (Range) y
First Second Third Fourth
< 13 13-18 19-23 >23
3.4 4.5 6.8 7.2
(0.2-7 +) (0.8-7 +) (0.6-7.2 +) (0.8-7.2 +)
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Table 3. Univariate acteristics at Study Characteristic
Wandering and falling Yes No Behavioral problems Yes No Hearing problems Yes No
Analysis of Relation between Entry and Survival
Patients
Median Median Survival Survival from from Entry Symptom Onset
n
y
Char-
Relative Risk (95% CI)
10 64
3.0 6.2
5.4 9.3*
3.1 (1.4 to 6.6)
66 56
4.3 6.0t
8.9 10.3t
1.5 (1.0 to 2.5)
31 94
4.0 5.3t
7.6 9.6t
1.5 (0.9 to 2.5)
* P < 0.005. t P < 0.05. The P values express the probability that the observed difference in median survival between patients with and without the characteristic occurred by chance, using the log-rank test.
was investigated. The combination of wandering and falling (relative risk, 2.1; CI, 0.9 to 5.2) and behavioral problems (relative risk, 1.4; CI, 0.7 to 2.9) at the time of evaluation appeared to have an independent effect on survival. After controlling for age and the other historical features, hearing impairment (a feature known to correlate with increasing age [19]) had no independent effect on survival. Discussion The survival of patients with Alzheimer-type dementia is highly variable. The length of survival from symptom onset in our cohort ranged from 1.8 to at least 16 years. Our study found that later age of onset, dementia severity, the combination of wandering and falling, behavioral problems, and possibly hearing problems were associated with shorter survival. Factors found not to influence survival were symptom duration, sex, depression, restlessness, comorbid conditions, vision problems, a reported decrease in appetite, the use of prescription drugs, and selected laboratory abnormalities (anemia, a serum folate level < 9 nmol/L, and an abnormal serum creatinine level). For 50% of our patients, survival from symptom onset was more than 9 years. The survival in this cohort is longer than other investigators have reported in part because of the different starting points used for calculating survival (symptom onset as opposed to study entry). The three studies measuring survival from study entry found a median survival of 3.4, 3.5, and 5.7 years, respectively (4, 6, 8), whereas those measuring survival from the onset of symptoms found a median survival of 7 and 8.1 years, respectively (5-7). Further, because this cohort was selected from outpatients, most of whom were having their first evaluation for dementia, our patients were probably less severely ill than those participating in previous studies. Reports on the association of age and survival have 432
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been inconsistent. Both Molsa and colleagues (8) and Barclay and associates (6) measured survival from study entry. The former group found no relation between age and survival and the latter reported that younger subjects had shorter survival time. Two studies that measured survival from symptom onset found that a later age of onset adversely affects survival (7, 20). Our study also found that a later age of onset adversely affects survival when measured from age at symptom onset, but that no relation exists when measured from study entry. This apparent discrepancy may be explained by the shorter symptom duration of older patients before presentation. This study confirms the report by Kaszniak and colleagues (10) that severity of illness, as measured by screening neuropsychologic tests, has a strong relation with survival. Brief, easily administered tests like the MMSE or mDRS correlate well with more detailed, prolonged neuropsychologic tests and can provide useful prognostic information. The combination of wandering and falling adversely affected survival in our cohort. The difference in median years of survival between patients who wandered and fell and patients who neither wandered nor fell was more than 3 years. This finding is not surprising. Patients with Alzheimer-type dementia are known to be at a considerable risk for falls and fractures compared with nondemented persons of the same age (21). Fractures tend to immobilize patients and place them at risk for other potentially lethal events (for example, pulmonary embolus and aspiration pneumonia). Consequently, effective strategies to control wandering and prevent falling in patients with Alzheimer-type dementia might help reduce morbidity and improve survival. As Barclay and colleagues (9) have also reported, the presence of behavioral problems portends a worse prognosis. Although the presence and number of such prob-
Figure 2. Survival curves for patients with Alzheimer-type dementia who had a history of wandering and falling (n = 10, broken line) compared with patients with Alzheimer-type dementia who had no history of wandering or falling (n = 64, solid line).
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lems have been linked to worsening dementia (22), existing data do not explain how behavioral problems adversely effect outcome. The multivariate analysis suggests that behavioral problems are related to wandering and falling but are not as important in predicting survival. On the other hand, behavioral problems themselves and the treatment applied to control them may be responsible for poor outcomes. Sedative and hypnotic drugs used to treat agitation, for example, have been associated with falling and hip fractures (23). We believe the management of behavioral problems needs further study, including studies of interventions designed to effectively and safely ameliorate these difficult and frequently frustrating problems. Although hearing impairment has also been linked to cognitive decline in patients with Alzheimer-type dementia (24, 25), its relation with survival is unclear. The presence of hearing problems did portend a worse prognosis in our cohort. Although controlling for age reduced the statistical significance of the relation (P = 0.20), this finding does not mean that no association exists between hearing problems and survival. Research (including therapeutic trials) focused on the relation between hearing loss and survival could clarify the importance of the association. Some features found not to have an association with survival deserve comment. The fact that symptom duration, for example, had no bearing on survival, suggests that substantial heterogeneity exists among patients with Alzheimer-type dementia. Some of this heterogeneity probably relates to the disease. Patients with long symptom duration before evaluation did not die sooner than patients with short symptom duration. Host factors also probably play a role in Alzheimer-type dementia heterogeneity. Although the presence of comorbid conditions and use of prescription drugs did not affect survival, the relatively small sample (especially the size of subgroups) and the measures used in our study may not have been powerful enough to detect a difference. On the other hand, age at symptom onset did affect survival suggesting that vigor and other host factors associated with age are important determinants of outcome. Our study had two main limitations. First, because this was a preliminary investigation, many variables were tested for a relation with survival. This strategy allows for the chance appearance of a significant finding simply because many were tested. However, most of the associations are logical and are supported by existing data. In addition, we did limit our analysis to variables selected a priori before analysis from a larger list of variables. Second, because the actual cause of death was not investigated, inferences from our results must be tempered. There is no information with regard to the direct causal role of those characteristics we found to be related to survival. Thus, it is entirely possible, for example, that wandering and falling serves as a marker for some other risk factor and that preventing falls would have no effect on mortality. Results from our study should provide useful information about the clinical course of Alzheimer-type dementia. For physicians, patients, and their families, measures of severity, like the MMSE, do provide accu-
rate prognostic information. For caregivers, the results support the common sense notion that efforts should be made to prevent or minimize falling. We hope our findings will stimulate other investigators to determine whether these results are generalizable to other populations. Acknowledgments: The authors thank Burton Reifler, MD; Shuzo M. Sumi, MD; and Suzanne Woo, PhD, for helping to collect the cohort; Connie Canfield, RN; Nina Chinn, RN; and Pam McLean, RN, for following the patients; and Jim Hughes, MS, and Duane Beekly for assisting with data analysis. The authors also thank the patients and their families for their participation and cooperation. Grant Support: In part by grants from the National Institute on Aging (AG05136; AG06781)—Alzheimer Disease Research Center, and the Alzheimer Disease Patient Registry. Requests for Reprints: Eric B. Larson, MD, MPH, Medical Director's Office, RD-30, University of Washington, Seattle, WA 98195. Current Author Addresses: Dr. Welch: Dartmouth-Hitchcock Medical Center, Center for Evaluative Clinical Sciences, Department of Community and Family Medicine, Hanover, NH 03756. Mr. Walsh: Department of Medicine, University of Washington, Seattle, WA 98195. Dr. Larson: Medical Director's Office, RD-30, University of Washington, Seattle, WA 98195.
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tropic drug use and the risk of hip fracture. N Engl J Med. 1987; 316:363-9. 24. Uhlmann RF, Larson EB, Koepsell TD. Hearing impairment and cognitive decline in senile dementia of the Alzheimer's type. J Am Geriatr Soc. 1986;34:207-10. 25. Uhlmann RF, Larson EB, Rees TS, Koepsell TD, Duckert LG. Relationship of hearing impairment to dementia and cognitive dysfunction in older adults. JAMA. 1989;261:1916-9.
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