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The Natural History of Alzheimer's Disease: A Brain Bank Study Journal of the American Geriatrics Society - Volume 43, Issue 11 (November 1995) - Copyright 1995 American Geriatrics Society

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CLINICAL INVESTIGATION The Natural History of Alzheimer's Disease: A Brain Bank Study
Barbara C. Jost MS George T. Grossberg MD Saint Louis University School of Medicine Department of Psychiatry and Human Behavior, Division of Geriatric Psychiatry, St. Louis, Missouri. OBJECTIVE: To define the natural history of Alzheimer's Disease (AD), from time of clinical (presumptive) diagnosis and/or onset of symptoms to death and to describe demographic and clinical characteristics of patients with AD. DESIGN: Retrospective medical records review. SETTING: Regional brain bank operated by a university hospital. PARTICIPANTS: One-hundred randomly selected, autopsy-confirmed Alzheimer's Disease patients. MEASUREMENTS: All information pertaining to family and clinical history (diagnoses, office visits, hospitalizations), medication use, nutritional status, and clinical testing (laboratory testing, imaging, diagnostics, and psychometric testing) was abstracted. Time of onset for behavioral symptoms (e.g., anxiety, wandering, agitation) and deficits in cognitive function (e.g., recent memory, concentration, language) and activities of daily living (ADL) were also abstracted. Data was collected on-site using a laptop computer and a series of customized data entry spreadsheets. Upon completion of the data abstraction process, data was converted to a database program for query and analysis. For editorial comments see p 1314 RESUlTS: A complete natural history timeline was constructed based on the mean values observed in order to demonstrate important clinical endpoints, namely, diagnosis, institutionalization, and death. The mean time between onset of symptoms and clinical diagnosis was 32.1 months (standard deviation = 37.9 months). The interval between symptom onset and AD diagnosis was longer for patients who were less than 65 at time of diagnosis (mean = 37.6 months), female patients (mean = 34.9 months), and patients with a positive family history of dementia (mean = 37.5 months). The mean age at diagnosis was 74.7 years (standard deviation = 8.6 years), with a range of 52 to 89 years. Most patients were diagnosed between the ages of 70 and 79. Males were diagnosed at an earlier age, 72.8 years, on average, than females, 75.4 years. The mean time to institutionalization from time of clinical diagnosis was 23.9 months (standard deviation = 33.6 months). The average age at institutionalization was 77.6 years, with a minimum of 60 years and a maximum of 92.5 years. Institutionalization occurred 56.5 months after symptom onset, on average. This interval was shorter among patients with a negative family history (mean = 53.1 months) and patients diagnosed after age 65 (mean = 51.6 months). Patients diagnosed before age 65 experienced a significantly greater average time to institutionalization, 94 months ( P = .01). Disease duration was measured as time from symptom onset until death. Mean disease duration was 101.3 months, or nearly 8.5 years (standard deviation = 59.2 months). Subgroup analysis showed that disease duration was prolonged in younger onset patients (mean = 129.1 months), females (mean = 107.9 months), and patients with a positive family history of dementia (mean = 106.3 months). CONCLUSIONS: These data suggest that the typical AD patient is diagnosed 32 months after symptom onset, at the age of 75 years. This patient is institutionalized 25 months after diagnosis, or approximately 57 months after symptom onset at age 78. The patient remains institutionalized for 44 months or, in actuality, until death. Total disease duration for this typical AD
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patient is just over 101 months, or approximately 8.5 years. This research was supported by The Mattson Jack Group and Cerenex, Inc. Address correspondence and reprint requests to Dr. George T. Grossberg, Director, Department of Psychiatry and Human Behavior, Division of Geriatric Psychiatry, Saint Louis University Health Sciences Center, 1221 S. Grand Blvd., St. Louis, MO 63104. Tel: 314-577-8726; Fax: 314-664-7248. [fig1]1 Patients with a family history of dementia. [fig1]2 Age at diagnosis. [fig1]3 Time to institutionalization. [fig1]4 Natural history timelines: Subgroup analysis. The natural history of Alzheimer's Disease (AD) has not been studied formally in large numbers of autopsy confirmed cases, Natural history studies are complex and are, by definition, longitudinal in design. These studies are complex, first of all, because a clinical diagnosis of Alzheimer's Disease is still based on exclusion. No fully validated diagnostic exists; autopsy remains the only method of confirming an Alzheimer's Disease diagnosis. Few long-term natural history studies have been reported in the literature. Those identified have had various objectives, and the natural history of AD has not been a focal point. Becker et al. [1] recently reported the results of a study of 181 individuals with probable AD who were followed for 5 years. The main objective of this study was to test the validity of a diagnostic classification schema rather than to define the natural history of AD. Survival times were analyzed; neither sex, years of education, nor pattern of cognitive impairment were related to survival. Annual rates of decline in cognitive function were calculated for a cohort of 20 patients over 3 years by Salmon et al. [2] This study found no correlation between decline in year one and rates of decline later in the

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course of the disease. A third longitudinal study of cognitive decline using the Blessed test found that age of onset, duration of illness, and family history of dementia had no significant influence on disease progression. [3] The Predictors Study, a longitudinal study conducted at three independent sites, was designed for the purpose of developing a predictive model of the natural history of AD. A total of 224 patients with early probable AD were followed at 6-month intervals. [4] The mean duration of illness among this cohort was 4.26 years. A number of natural history studies are in progress. The well known Framingham cohort is the subject of a study of dementias, including probable AD, by Bachman et al. [5] These cases will be used to study precursors of AD as well as its natural history. Two European natural history studies are also underway. The Medical Research Council Multicentre Study of Cognitive Function and Aging is designed to compare prevalence and incidence of dementia at five centers in the UK; data from all centers will be used to construct a natural history of cognitive decline. Patients will be examined twice, with an interval of 2 years between exams. A 20% subsample will be reviewed in more detail. [6] The Kungsholmen Project in Stockholm is also a population-based study, and involves 2368 inhabitants aged 75 years and older; persons identified as probable dementia cases will be followed. [7] Alzheimer's brain banks are a suitable platform for the investigation of the natural history of AD. These brain banks have been established to provide family members with a precise diagnosis of AD and to facilitate research efforts. A survey completed in March 1991 identified 44 AD brain banks operating in the United States alone. [8] Brain bank registrants with suspected Alzheimer's Disease are an ideal cohort for a natural history study. The Saint Louis University Alzheimer's Association Brain Bank (SLU-AABB) was established in August 1985 through a seed grant from the St. Louis Chapter of the Alzheimer's Association. SLU-AABB is a regional brain bank open to all families in the St. Louis metropolitan area, including outstate Missouri and Illinois. Staff members include a geriatric psychiatrist, neuropathologist, a coordinator, and a research assistant. Potential SLU-AABB registrants are identified through the Saint Louis University Division of Geropsychiatry clinic and by clinicians, nursing staff, and caregivers who are made aware of the service by the widespread dissemination of informative SLUAABB brochures. Persons with a clinical diagnosis of Alzheimer's Disease are registered before death. A very small number of registrants are registered upon death. At the time of registration, four steps are taken: 1. Permission is received to perform a postmortem examination, limited to the brain only, from the registrant's next of kin or legal guardian. 2. Release of information forms are signed in order to obtain the registrant's medical history. Signed forms are sent to the primary care physician, the physician who made the diagnosis of Alzheimer's Disease, and any hospital or nursing facility that treated the registrant.
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3. A detailed questionnaire is sent to the primary caregiver for the collection of biographical information, family and medical history, and chronology of symptoms. 4. An instruction form, outlining the procedures to be followed at the time of death, is sent to the nursing facility or the primary caregiver. At the time of death, the registrant's head is packed in ice, and the body is transported to Saint Louis University Hospital by a transport company notified by the nursing facility or the primary caregiver. Upon completion of the autopsy, the body is picked up by the funeral home or next of kin. Results of the autopsy are sent to the next of kin within 6 weeks. The cost of transportation and autopsy is subsidized for families requiring financial assistance. As of year end 1992, 435 persons with a clinical diagnosis of Alzheimer's Disease had been registered in the SLU-AABB. Of these, autopsy had been performed on 250. The SLU-AABB is accruing registrants at the rate of 2 to 3 per week.

OBJECTIVES AND METHODS

The primary objective of this study was to define the natural history of Alzheimer's Disease from time of clinical (presumptive) diagnosis to death. A further objective was to identify potential risk factors, comorbidities, and points of therapeutic intervention. Approval to execute this study was obtained from the Institutional Review Board at Saint Louis University. Registrants in the SLU-AABB were considered eligible for this study if the diagnosis of Alzheimer's Disease was confirmed by autopsy and if the medical chart was complete. Clinical diagnosis was made either by the patient's private physician or by a geropsychiatrist at the Saint Louis University Division of Geropsychiatry clinic. Histopathological diagnosis was made by the staff neuropathologist on the basis of the criteria established by Dr. Zaven S. Khachaturian and expert panel in 1985. [9] A chart was considered complete if it contained records dated no less than 2 months before their death. Most charts contained records from clinical diagnosis until death, with no major chronological discontinuities. Many charts contained records before clinical diagnosis. The word "diagnosis" from this point on will refer to the clinical (presumptive) diagnosis. One-hundred charts were randomly selected for study. Of these, five were chosen, again at random, for inclusion in a pilot study. The purpose of the pilot study was to test the data abstraction and data entry methodologies described below. Data entry was accomplished using a portable personal computer (AST, 386SX). A series of 14 data entry screens was designed in Excel for Windows , a spreadsheet program.

A unique identification number was used to link data contained on different worksheets to a specific chart. Date of birth, date of clinical diagnosis, date of institutionalization, date of death, and sex were compulsory entries and could not be left blank. Information pertaining to clinical history, medication use, nutritional status, and clinical testing (laboratory testing, imaging, diagnostics, and psychometric testing) was abstracted and entered into the corresponding worksheet shown in Appendix A. ICD-9CM codes (see Clinical History Sheet, Appendix A) were abstracted from the medical record where available. In most cases, however, the ICD-9-CM code was not documented in the medical record. An electronic "look-up" file was used to assign an ICD-9CM code to each diagnostic description.

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Behavioral symptomatology and deficits in cognitive function and activities of daily living (ADL) were documented in the corresponding worksheet (Appendix A). The date a symptom or deficit was first noted was typically found in the physician's notes (from the caregiver interview) or in hospital or nursing home admission notes. These dates were abstracted from the chart and entered into the appropriate field. The actual date of first manifestation, or symptom onset, was not available in the majority of cases. Approximate dates given by persons acting as the primary historian, usually the patient's caregiver, were converted to month/day/year format according to the following rules: (1) any date given as a year only was converted to 06/01/YY format; (2) any date given as a month/year was converted to MM/15/YY format. Caregivers commonly cited dates of symptom onset relative to a holiday, e.g., "We first noticed Mother's wandering last Christmas." or "Dad got lost driving to the Labor Day picnic." In the first example, the entry "12/25/92" was entered in the field labeled "Wandering" in the Behavioral Symptoms Sheet. In some instances, a symptom or deficit was noted to be present, but the date of onset was not known or not documented (e.g., "has experienced hallucinations"). In these cases, the entry "HX" was made in the date field, denoting that the symptom or deficit had occurred at some time in the patient's history. In the final statistical analysis, all HX entries were converted to the date of clinical diagnosis entered in the Bio Sheet.
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Data from the completed worksheets was imported into a Windows-compatible database, ACCESS TM , for statistical analysis and summary. Each date field was expressed as months before/after diagnosis, calculated as ([date]-[date of diagnosis])/30. A negative number means the event preceded diagnosis; a positive number means the event was recorded after diagnosis.

RESULTS
Patient Demographics The study population was comprised of 72 females and 28 males, a ratio of 2.6:1. All patients were white. Family income was known for 41% of the sample and was relatively evenly distributed between low (less than $20,000) and high (greater than $35,000). Occupation was known for 85% of the sample. All occupations were classified using a system based on US census categories: managerial and professional; technical sales and administration; service workers; farming, forestry, fishing; manufacturing, craft, and repair; operatives, fabricators, and laborers. The category "homemaker" was added. White collar and blue collar occupations were equally represented (42 vs 43). About 40% of patients in the database for whom occupation was known were homemakers, a reflection of the preponderance of females in the study sample and the time period when most were in the work force (1930s to 1960s). The mean number of years of education attained was 11.7 years, with a range of 6 to 20 years. Educational level was not known for 40% of the patients surveyed. Smoking and Alcohol Lifetime smoking status was known for almost all patients in the sample (99%). A total of 65 (65.7%) patients had never smoked. The mean number of years smoked was 34 years for the 34 patients who had smoked at some time in their lives. Alcohol consumption was known for 65 of the patients surveyed. A total of 24 patients (37%) reported no consumption of alcohol. Five patients were known to be heavy drinkers, defined as having consumed more than two drinks per day. Family History of Dementia and Down's Syndrome A total of 43 patients had a family history of dementia; 15 of these patients (35%) had a multiple family history (more than one relative with dementia). About 37% of those with a positive family history of dementia had a mother with dementia (Figure 1) . Five patients were known to have a family history of Down's syndrome. Onset of Symptoms Onset of symptoms was calculated, for each patient, as the earliest date appearing in the ADL, Behavioral Symptoms, and Cognitive Deficits worksheets or the date of diagnosis, whichever was earliest. Onset of symptoms varied from more than 13 years before diagnosis (158 months) to coincident with diagnosis among 93 evaluable patients (seven patients with onset of symptoms greater than 2 standard deviations from the mean were excluded from this analysis). The mean time of onset of symptoms was 32.1 months before diagnosis (standard deviation = 37.9 months); the mean and standard deviation were 45.7 and 62.5 months, respectively, with outliers included. Symptom onset was earlier for patients who were less than 65 at time of diagnosis (mean = 37.6 months), female patients (mean = 34.9 months), and patients with a positive family history of dementia (mean = 37.5 months) (Table 1) . Clinical Diagnosis The mean age at diagnosis was 74.7 years (standard deviation = 8.6 years), with a range of 52 to 89 years. Most patients were diagnosed between the ages of 70 and 79 (Figure 2 , Table 2) . Males (mean = 72.8 years) were diagnosed at an earlier age than females. Institutionalization A total of 85 patients were institutionalized at some time during the course of the disease. Most of these patients, 87% (n = 74), were institutionalized at the time of diagnosis or after diagnosis. Institutionalization was coincident with diagnosis in eight patients (Figure 3) . Excluding outliers, the mean

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Figure 1. Patients with a family history of dementia.

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TABLE 1 -- Symptom Onset Months Before Diagnosis All patients, excluding outliers (n = 93) Younger at diagnosis, <65 (n = 12) Older at diagnosis, 65 (n = 81) Diagnosed between 65 and 74 (n = 25) Diagnosed between 75 and 84 (n = 49) Diagnosed 85 (n = 7) Males (n = 26) Females (n = 67) Family history of dementia (n = 38) Negative family history of dementia (n = 55) SD = standard deviation, Min. = minimum, Max. = maximum. Mean 32.1 37.6 31.3 31.9 31.3 28.8 24.8 34.9 37.5 28.3 SD 37.9 45.1 36.9 36.1 37.7 39.8 26.3 41.3 40.4 35.9 Min. 158.3 132.4 158.3 133.9 158.3 97.1 109.6 158.3 158.3 132.4 Max. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

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Figure 2. Age at diagnosis.

TABLE 2 -- Age at Diagnosis Mean All patients (n = 100) Males (n = 28) Females (n = 72) Family history of dementia (n = 43) 74.7 72.8 75.4 74.9 8.6 9.4 8.2 7.4 9.4 Age (years) SD Min. 52.0 53.0 52.0 52.0 53.0 Max. 89.0 84.0 89.0 85.3 89.0

Negative family history of dementia (n = 57) 74.5 SD = standard deviation, Min. = minimum, Max. = maximum.

time to institutionalization from time of symptom onset was 56.5 months (n = 78; standard deviation = 48.0 months); the mean and standard deviation were 72.6 and 71.9 months, respectively, for the group as a whole. Time to institutionalization

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Figure 3. Time to institutionalization.

was significantly prolonged for patients less than 65 years of age at time of diagnosis (mean = 94.0 months; P = .01). Patients who were older than 65 years at diagnosis (mean = 51.6 months), females (mean = 55.8 months), and persons with a negative family history (mean = 53.1 months) were institutionalized earlier in the course of the disease than the typical Alzheimer's patient (Table 3) . The mean time to institutionalization from time of clinical diagnosis was 23.9 months (standard deviation = 33.6 months). This was also prolonged for patients less than 65 years at time of diagnosis (mean = 45.5 months compared with 23.9 months, P = .05). Patients who were older than 65 years of age at diagnosis (mean = 21.4 months) and females (mean = 22.7 months) were institutionalized sooner after diagnosis than the average patient (Table 3) . The average age at institutionalization was 77.6 years, with a minimum of 60 years and a maximum of 92.5 years (Table 4) . Patients diagnosed before age 65 were also institutionalized at an earlier age (mean = 62.5 years, n = 9). This difference was highly statistically significant. Conversely, those diagnosed between ages 75 and 84 and older than age 85 entered institutional care later, at age 80.5 and 87, respectively ( P < .03, P < .003). Disease Duration Disease duration was measured as time from symptom onset until death. Mean disease duration was 101.3 months, or nearly 8.5 years (standard deviation = 59.2 months). Five patients were excluded from the analysis as outliers (disease duration was greater than 2 standard deviations from the mean); the mean and standard deviation were 111.2 and 72.1 months, respectively, including outliers. The longest disease duration was 252.1 months, or more than 21 years. In the subgroup analysis, disease duration was longest among younger onset patients (mean = 129.1 months). Disease duration was also prolonged among females (mean = 107.9 months) and patients with a positive family history of dementia (mean = 106.3 months) (Table 5) .

DISCUSSION
The diagnosis of AD can occur months, sometimes years, after the actual time of symptom onset. The mean time of onset of symptoms for the cohort described here (93% of patients were evaluable) was 32.1 months before clinical

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TABLE 3 -- Time to Institutionalization Months Before/After Onset of Symptoms Mean SD Min. Max. All institutionalized patients, excluding outliers (n = 78) 56.5 48.0 -91.3 170.5 Younger at diagnosis, <65 (n = 9) 94.0 (1) 41.5 34.7 153.1
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Older at diagnosis,

65 (n = 69)

51.6 58.9 55.8 62.2 53.1

46.9 45.5 49.1 39.0 52.8

-91.3 170.5 0.0 168.0 -91.3 170.5 11.4 170.5 -91.3 168.0

Males (n = 17) Females (n = 61) Family history of dementia (n = 29) Negative family history of dementia (n = 49) Notes: 1: P = 0.01

Months Before/After Clinical Diagnosis Mean All institutionalized patients (n = 85) Younger at diagnosis, <65 (n = 9) Older at diagnosis, Males (n = 19) Females (n = 66) Family history of dementia (n = 34) Negative family history of dementia (n = 51) Notes: 2: P = 0.05
*

SD 33.6 31.6 33.0 28.7 34.9 32.2 34.8

23.9 45.5 (2) 21.4 28.2 22.7 23.8 24.0

Min. Max. -92.4 106.5 6.5 106.5 -92.4 95.8 0.0 106.5 -92.4 95.8 -73.9 91.6 -92.4 106.5

65 (n = 76)

SD = standard deviation, Min. = minimum, Max. = maximum.

*Negative value denotes time before diagnosis.

TABLE 4 -- Age at Institutionalization Mean 77.6 62.5 79.4 74.3 80.5 87.0 76.6 77.9 78.6 77.0 76.6 78.7
*

All institutionalized patients (n = 85) Younger at diagnosis, <65 (n = 9) Older at diagnosis, 65 (n = 76) Diagnosed between 65 and 74 (n = 20) Diagnosed between 75 and 84 (n = 50) Diagnosed 85 (n = 15) Males (n = 19) Females (n = 66) Family history of dementia (n = 34) Negative family history of dementia (n = 51) Sx onset < 24 mo. before diagnosis (n = 43) Sx onset 24 mo. before diagnosis (n = 42) Notes: SD = standard deviation, Min. = minimum, Max. = maximum.

Age (years) SD Min. 6.9 60.0 1.7 4.8 3.9 3.0 3.9 7.7 6.8 5.0 7.9 7.8 5.9 60.0 67.6 67.6 74.5 82.7 60.7 60.0 65.8 60.0 60.0 62.9

Max. 92.5 65.8 92.5 80.5 86.1 92.5 86.1 92.5 86.1 92.5 89.9 92.5

* *

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* P << 0.001; ** P < 0.03; *** P < 0.003.

diagnosis. There are many possible reasons for this lag in detection. The difficulties associated with making a diagnosis of AD play a major role. Concomitant diseases and/or the consequences of the aging process, such as depression, hearing, and visual loss, are often used to explain the observed changes in cognitive function. Denial on behalf of the primary caregiver often plays a role ("it's just senility" or "hardening of the arteries"). Time to diagnosis from symptom onset was longer for patients who were less than age 65 at the time of diagnosis (mean = 37.6 months). It is possible that younger patients are better able to "cover-up" their disease or that spouses and children are more apt to deny that anything is wrong in a younger patient. Persons with a positive family history of dementia were also diagnosed later in their disease, an average of 37.5 months after symptom onset. One possible explanation may be that familial cases of AD are characterized by a different symptom complex, with disease onset of a more insidious nature. Family members who are cognizant of the increased risk of AD afflicting their family may also have a more fatalistic attitude toward AD, thus causing them to seek help later in the course of the disease. Diagnosis was also

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TABLE 5 -- Disease Duration (Symptom Onset to Death) Months Mean SD Min. All patients, excluding outliers (n = 95) Younger at diagnosis, <65 (n = 12) Older at diagnosis, 65 (n = 83) Males (n = 26) Females (n = 69) Family history of dementia (n = 39) 101.3 129.1 97.3 84.0 107.9 106.3 59.2 58.7 58.5 47.4 62.1 60.2 58.7 1.7 47.1 1.7 1.7 3.9 1.7 3.9

Max. 252.1 252.1 251.9 204.9 252.1 251.9 252.1

Negative family history of dementia (n = 56) 97.9 SD = standard deviation, Min. = minimum, Max. = maximum.

delayed among female patients (mean = 34.9 months from time of symptom onset). Unwillingness of the husband to seek medical attention, consistent with the lower rate of physician consultation by men in general, could be a factor. This postulate gains more credence when one compares the time to diagnosis of females with that of males (34.9 months vs 24.8 months); though this difference appears large, it was not statistically significant. The average age at diagnosis was 74.7 years among the cohort as a whole. Males were diagnosed earlier in life, at 72.8 years on average. Hormonal protection, for example, estrogen, may be a contributing factor, though much larger studies are needed to establish this relationship. The observed difference in age at diagnosis could also be indicative of an alternative pathogenesis in males. The majority of patients, 85% of the cohort, were institutionalized at some time during the course of the disease. A study conducted by Berg et al. [10] reported that 84% of patients (n = 43) with mild AD at study entry were placed in a nursing home by the seventh year of follow-up. The mean time to institutionalization from time of symptom onset was 56.5 months for this entire cohort. Time to institutionalization was significantly longer for patients who were younger than age 65 at diagnosis (mean = 94.0 months, P = .01). The nine patients in this subgroup (institutionalized and younger than 65 at diagnosis) were institutionalized more than 7.5 years after onset of symptoms. Institutionalization was also delayed among patients with a positive family history of AD; this group was institutionalized 62.2 months after symptom onset, on average. The mean disease duration among all evaluable patients, defined as the time elapsed between symptom onset and death, was 101.3
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months, or nearly 8.5 years. This is consistent with the value of 9.3 years calculated by Walsh et al. [11] Patients who were younger at diagnosis (<65) experienced a longer disease duration than the group considered as a whole (mean = 129.1 months). Bracco et al. [12] recently reported a mean survival from symptom onset of 10.6 years (127 months) for patients with early-onset disease (onset before or at age 65) and 7.3 years (88 months) for patients with late-onset disease (onset after age 65). These values compare favorably with the findings of this study (127 vs 129.1 and 88 vs 97.3 months for early and late-onset, respectively) although AD was confirmed by autopsy in only seven of 115 patients. The longer disease duration noted among females (mean = 107.9 months) and persons with a positive family history (mean = 106.3 months) may be evidence for a distinct

Figure 4. Natural history timelines: Subgroup analysis.

pathology in these groups. On the other hand, a natural history study involving 181 individuals reported no sex difference in survival. [13] The natural history timelines of important clinical subgroups are depicted in Figure 4 . This figure graphically depicts three important clinical events, namely, diagnosis, institutionalization, and death, for the group as a whole and for various subgroups. The "average" AD patient was diagnosed 32 months after symptom onset, at the age of 75 years. This patient was institutionalized 25 months after diagnosis, or approximately 57 months after symptom onset at age 78. The patient remained institutionalized for 44 months, or, in actuality, until death. Total disease duration for this average AD patient was just over 101 months, or approximately 8.5 years. Future analyses of this data set will investigate the role of education, medical history, and cognitive, behavioral, and functional impairment on disease duration and important clinical endpoints. REFERENCES

1. Becker

JT, Boller F, Lopez OL et al. The natural history of Alzheimer's disease. Description of study cohort and accuracy of diagnosis. Arch Neurol

1994;51:585-594
2. Salmon

DP, Thal LJ, Butters N et al. Longitudinal evaluation of dementia of the Alzheimer type: A comparison of 3 standardized mental status

examinations. Neurology 1990;40:1225-1230

3. Ortof 4. Stern

E, Crystal HA. Rate of progression of Alzheimer's disease. J Am Geriatr Soc 1989;37:511-514 Y, Folstein M, Albert M et al. Multicenter study of predictors of disease course in Alzheimer disease (the "Predictors Study"). I. Study design,

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cohort description, and intersite comparisons. Alzheimer Dis Assoc Disord 1993;7:3-21

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DL, Wolf PA, Linn RT et al. Incidence of dementia and probable Alzheimer's disease in a general population; The Framingham study.

Neurology 1993;43(part 1 )1:515-519

6. Chadwick

C. The MRC Multicentre Study of Cognitive Function and Aging: a EURODEM incidence study in progress. Neuroepidemiology

1992;11(suppl. 1):37-43
7. Fratiglioni

L, Viitanen M, Backman L et al. Occurrence of dementia in advanced age: The study design of the Kungsholmen Project.

Neuroepidemiology 1992;11(suppl 1):29-36

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M, Dowd DM, Grossberg GT et al. Survey of U.S. Alzheimer brain banks: A 1990 directory. Alzheimer Dis Assoc Disord 1990;5:188-

193.
9. Khachaturian 10. Berg

Z. Diagnosis of Alzheimer's Disease. Arch Neurol 1985; 42:1097-1105

L, Miller JP, Storandt M et al. Mild senile dementia of the Alzheimer type. 2. Longitudinal assessment. Ann Neurol 1988;23:477-484 JS, Welch HG, Larson EB. Survival of outpatients with Alzheimer-type dementia. Ann Intern Med 1990;113:429-434 L, Gallato R, Grigoletto F et al. Factors affecting course and survival in Alzheimer's disease: A 9-year longitudinal study. Arch Neurol

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12. Bracco

1994;51:1213-1219
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JT, Boller F, Lopez OL et al. The natural history of Alzheimer's disease. Description of study cohort and accuracy of diagnosis. Arch Neurol 1994;51:585-594

APPENDIX A
DATA ABSTRACTION WORKSHEETS Bio Sheet (biographical information) ID no. Date of birth Date of (clinical) diagnosis Date of institutionalization Date of Death Sex Race/Ethnicity Payor Family income Educational level Occupation before retirement Date of retirement Marital status Parity Allergies Smoking status Caffeine (consumption per day)
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Alcohol (consumption per day) Family history (diseases/conditions known to have affected any family members) Mother's date of birth Clinical History Sheet ID no. Disease/condition ICD-9-CM Date of diagnosis Surgical procedure Date performed Psychiatric treatment Date of administration Date of admission to hospital Date of discharge from hospital Physical Exam Sheet ID no. Date Weight Systolic blood pressure Diastolic blood pressure Pulse Temperature Observation Nutrition Sheet ID no. Date Weight Meals/day Caloric intake Special diet Vitamin/mineral supplementation Meds Sheet
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ID no. Date Generic Brand Form Strength Units per dose Doses per day Amount Refills Adverse events Chemistry Sheet 1 ID no. Date (SMAC-23) Chemistry Sheet 2 ID no. Date (urinalysis) (thyroid panel) Hematology Sheet ID no. Date (CBC) Imaging Sheet ID no. Date Type Outcome/comments Diagnostics Sheet ID no. Date Type
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Outcome/comments Psychometrics Sheet ID no. Date Mini-Mental Geriatric Depression Scale Activities of Daily Living Clock drawing Neuropsychiatric testing Behavioral Symptoms Sheet ID no. Paranoia Delusions Hallucinations Wandering Aggression

P1255

Diurnal rhythm Mood change Depression Anxiety/phobia Accusatory behavior Agitation Irritability Sexually inappropriate behavior Socially unacceptable behavior Social withdrawal Cognitive Deficits Sheet ID no. Concentration Recent memory Remote memory
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Orientation Praxis Language Psychomotor Calculations Activities of Daily Living Sheet ID no. Bathing/grooming Bookkeeping Dressing Driving/transportation Eating Exercise Food preparation Hearing Housekeeping Medication Mobility Phone Shopping Social activities Speech Toileting Vision Writing

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