Treatment of spondylolysis and spondylolisthesis in children and adolescents

The treatment of spondylolysis and spondylolisthesis in children depends on the severity of clinical symptoms, pathologic anatomy, and prognosis. Simple spondylolysis can be cured by immobilization alone in selected cases, or by surgery when it remains symptomatic and resistant to nonoperative treatment. The majority of cases are asymptomatic and require no treatment. Spondylolisthesis is classified into 2 types based on the magnitude of the lumbosacral angle: spondylolisthesis with a horizontal sacrum (lumbosacral angle > or = 100 degrees), which seldom requires surgical treatment, usually responds to orthotic management, and generally shows little progression; spondylolisthesis with a vertical sacrum (lumbosacral angle < 100 degrees) which is always progressive, can produce neurologic impairment and cosmetic and functional disability, and requires surgical treatment. In 17 cases the author has reduced the latter deformity by gradual traction in hyperextension followed by cast immobilization, then stabilized the reduction by posterolateral fusion performed through the cast without instrumentation and without opening the spinal canal. When the lumbosacral angle is not improved to 100 degrees or more by hyperextension and traction, an anterior console interbody fusion is added before the posterolateral fusion.     

SPECT evaluation of lumbar spondylolysis and spondylolisthesis

Fifty patients with back pain and radiologically diagnosed spondylolysis were evaluated by a single-photon emission computed tomography (SPECT bone scanning). These patients were separated into three groups according to the degree of spondylolisthesis accompanying the spondylolysis. The data obtained from the study indicate that in acute spondylolysis, the SPECT scan is positive at the pars interarticularis. As the spondylolysis becomes chronic, the SPECT scan tends to revert toward normal even though healing of the spondylolysis has not occurred. As spondylolisthesis develops and progresses, the SPECT scan again becomes positive. The positivity, however, is more anterior and more diffuse. The authors propose that SPECT scanning in spondylolysis is not a positive or negative process, but rather varies with the time and stability of the spondylolytic spine.     

Defects of pars interarticularis in athletes: a protocol for nonoperative treatment

The purpose of this study was to report the results of a specific treatment protocol for athletes with spondylolysis or spondylolisthesis of the lumbar spine. A retrospective study with recent follow-up was performed on 82 patients treated with restriction of activity, bracing, and physical therapy. All of the patients were involved in sports at first onset of symptoms. Sixty-six patients were boys and 16 were girls. Activities involving repetitive hyperextension and/or extension rotation of the lumbar spine were described as painful in 98% of the patients. Of the 62 patients with spondylolysis, 53 (85%) had an L5 defect and nine (15%) an L4 defect (90% of these 62 patients' defects were located in the most caudad mobile vertebra). Thirty-seven patients had bilateral pars defects, and 25 had unilateral defects. Eight patients had normal roentgenograms, but these eight had abnormal bone scans. Nine patients with spondylolysis underwent posterolateral fusion. Average follow-up was 4.2 years. Fifty-two (84%) had excellent results, eight had good results, and two had fair results. Twenty patients had a spondylolisthesis: 12 were grade I, six were grade II, and two were grade III. Twelve patients (60%) required surgery; 9 had excellent results, one had good results, one had a fair result, and one had a poor result. Pars defects must be suspected in the differential of low back pain in young athletes. Oblique radiographs are frequently diagnostic; however, if the history and examination are suggestive despite normal plain films, a bone scan should be obtained. Nonoperative management of pars defects is frequently successful.(ABSTRACT TRUNCATED AT 250 WORDS)     

Spondylolisthesis in children and adolescents

A study of spondylolysis and spondylolisthesis in 142 children and adolescents is reported. In twelve of the seventy-nine patients followed for over a year the affected vertebra slipped further by 10 per cent or more. Increasing slip occurred mainly during the adolescent growth spurt, and was greater when spinal bifida or other vertebral anomalies were present. If at presentation the slip is less than 30 per cent then further slip beyond 30 per cent is unlikely. Decompression posteriorly is advised when signs of nerve pressure are present. Indications for spinal fusion are suggested; the intertransverse method of fusion was used in sixty-nine patients.     

Spondylolisthesis in childhood and adolescence

Isthmic spondylolisthesis occurs in 4.4% of children. In general it is a benign condition. The majority of individuals with mild or moderate isthmic vertebral slip remain free of symptoms or get only mild symptoms. In children and adolescents with mild slip, primary treatment of pain symptoms is non-operative. Young children before the growth spurt need radiological follow-up for documentation of possible slip progression. If the slip exceeds 25% in a child, segmental fusion to prevent further progression should be considered. Uninstrumented posterolateral fusion is the method of choice for treatment of pain symptoms not responding to conservative measures in slips up to 50%. In severe slips (> 50%), anterior or combined fusion is necessary to prevent further progression of lumbosacral kyphosis. The clinical and subjective results of in situ fusion in this age group are satisfactory in 80-90% of cases. Slip reduction is possible. It requires internal fixation and is connected with a higher risk of complications. The results of slip reduction have not yet been shown to be superior to results after in situ fusion. It may be performed in cases of spondyloptosis with severe impairment of function and sagittal malalignment of the spine.     

Evaluation of specific stabilizing exercise in the treatment of chronic low back pain with radiologic diagnosis of spondylolysis or spondylolisthesis

STUDY DESIGN: A randomized, controlled trial, test--retest design, with a 3-, 6-, and 30-month postal questionnaire follow-up. OBJECTIVE: To determine the efficacy of a specific exercise intervention in the treatment of patients with chronic low back pain and a radiologic diagnosis of spondylolysis or spondylolisthesis. SUMMARY OF BACKGROUND DATA: A recent focus in the physiotherapy management of patients with back pain has been the specific training of muscles surrounding the spine (deep abdominal muscles and lumbar multifidus), considered to provide dynamic stability and fine control to the lumbar spine. In no study have researchers evaluated the efficacy of this intervention in a population with chronic low back pain where the anatomic stability of the spine was compromised. METHODS: Forty-four patients with this condition were assigned randomly to two treatment groups. The first group underwent a 10-week specific exercise treatment program involving the specific training of the deep abdominal muscles, with co-activation of the lumbar multifidus proximal to the pars defects. The activation of these muscles was incorporated into previously aggravating static postures and functional tasks. The control group underwent treatment as directed by their treating practitioner. RESULTS: After intervention, the specific exercise group showed a statistically significant reduction in pain intensity and functional disability levels, which was maintained at a 30-month follow-up. The control group showed no significant change in these parameters after intervention or at follow-up. SUMMARY: A "specific exercise" treatment approach appears more effective than other commonly prescribed conservative treatment programs in patients with chronically symptomatic spondylolysis or spondylolisthesis.     

Evaluating the child with back pain

The most common causes of serious low back pain in children include spondylolysis, Scheuermann disease and musculoligamentous injury. Questions should be asked about the mechanism of onset and exacerbating factors, and the frequency, duration and severity of the pain. The examination should check gait and alignment, flexibility, strength and reflexes, and localize and evaluate the pain. Warning signs of serious problems include constant pain in a child younger than 11 years of age that lasts for several weeks or occurs spontaneously at night, repeatedly interferes with school, play or sports, or is associated with marked stiffness and limitation of motion, fever or neurologic abnormalities. Pain at the lumbosacral junction may suggest spondylolysis or spondylolisthesis. Scheuermann disease is diagnosed by the observance of wedging, irregularity or growth disturbance of three successive vertebrae. Musculoligamentous pain may result from injury to or overuse of muscles or joints of the back. Rare causes include discitis, tuberculosis, bone or spinal cord tumor, pyelonephritis and retroperitoneal infection.     

The electrocardiogram during physical stress and Holter monitoring in the detection of asymptomatic myocardial infarct

INTRODUCTION: In patients with myocardial infarction acute myocardial ischaemia could be manifested by characteristic ischaemic symptoms or noncharacteristic symptoms such as cardiac insufficiency or heart rhythm disturbances. Sometimes myocardial ischaemia is not followed by any symptom. This condition is known as asymptomatic myocardial ischaemia. Asymptomatic myocardial ischaemia usually could be detected by treadmill exercise tolerance test or 24-hour Holter ECG monitoring. PATIENTS AND METHODS: We analyzed a group of 58 patients suffering from myocardial infarction with ST segment depression during the treadmill exercise tolerance test. All patients were on Holter 24-hour ECG monitoring. As a criterion of myocardial ischaemia during Holter monitoring ST segment depression of 1 mm and more, lasting 1 minute and more, and 0.08" of J point was accepted. RESULTS: During the treadmill exercise tolerance test segment depression was not followed by any symptom in 18 (31%) patients. There were no differences in the number of patients with hypertension in the group with symptoms and the group without symptoms. Diabetes mellitus was more frequent in the group with asymptomatic myocardial ischaemia. The average values of maximum ST segment depression and heart rates during treadmill tests were not statistically significant in both groups (with and without symptoms). During daily activities myocardial ischaemia was found in 30 (51%) patients by a 24-hour Holter ECG monitoring. We observed 198 episodes of myocardial ischaemia of which 138 (69.1%) were asymtomatic. The amplitude of ST segment depression and duration of these changes were significantly greater in the group with symptomatic episodes than in the group with asymptomatic episodes of myocardial ischaemia. DISCUSSION: Asymptomatic myocardial ischaemia is an often appearance in patients with myocardial ischaemia. Almost in 25% of persons in whom sudden death occurred obstructive changes in coronary arteries during the autopsy were found. Asymptomatic myocardial ischaemia could be found even an a "completely healthy person" without any complaints. Asymptomatic myocardial ischaemia is usually detected in a "completely healthy person" by casual diagnosis, in patients with stable and non stable angina pectoris, in patients with stenosis of the coronary arteries proved by angiography, and in patients after myocardial infarction. Some authors considered that treadmill exercise tolerance testing is less reliable to discover asymptomatic myocardial ischaemia comparing to the continuous 24-hour Holter ECG monitoring. It is know that in patients with diabetes mellitus neuropathy precedes the onset of symptomatic myocardial ischaemia. Asymptomatic myocardial ischaemia has the same predictive value for prognosis of the disease as symptomatic myocardial ischaemia. In some patients "anginal alarm system" is defective, and perception and conduction of pain sensations are disturbed. CONCLUSION: 1. In 31% of patients who suffered from myocardial infarction with ST segment depression during the treadmill testing asymptomatic myocardial ischaemia was found. 2. By Holter monitoring ischaemia ST segment depression during the exertion is observed in 52% of patients. Most of ischaemic episodes were asymptomatic. 3. The amplitude of ST segment depression is significantly greater and duration of depression is significantly longer in symptomatic episodes of myocardial ischaemia comparing to asymptomatic myocardial ischaemia obtained by Holter ECG monitoring.     

Cervical spondylolysis in children. Apropos of 4 cases. Review of the literature

PURPOSE OF THE STUDY: A clinical and radiological study of four cases of spondylolysis in children. Literature review shows the congenital origin of the disorder and how it is to be treated. MATERIAL AND METHODS: We report on four children with cervical spondylolysis. One of the children presented a two-level spondylolysis C5C6. One case was totally asymptomatic and was hazardly discovered. Standard radiographs were used for diagnosis. Conservative treatment was administered in all cases and all patients were immobilized for a few days. DISCUSSION: It has been clearly established that cervical spondylolysis is a congenital disorder often associated with other anomalies: spina bifida, dysplasia of the posterior articular processes. In the child, cervical spondylolysis is only discovered in fifty per cent of Post traumatic cases. The most frequent finding is at C6. A diagnosis can be made based on the radiographs and the CT scan. MRI will only be indicated in spondylolisthesis in order to analyze the disc statement and the degree of canal narrowing. When possible conservative treatment should be adopted. Arthrodesis is reserved for unstable and painful lesions. CONCLUSION: Cervical spondylolysis in the child is a rare congenital disorder. It must be distinguished from the congenital absence of a pedicle and from a pedicle or isthmic fracture. It is a lesion which is normally discovered once the patient has turned adult and is very well long term tolerated.     

Dyspnoea and exercise intolerance during cardiopulmonary exercise testing in patients with univentricular heart. The effects of chronic hypoxaemia and Fontan procedure

BACKGROUND: Patients with univentricular hearts have decreased exercise tolerance and may demonstrate exertional dyspnoea. It is not known if chronic hypoxaemia exacerbates exercise intolerance and contributes to symptomatic limitation. The extent to which surgical correction of a right-to-left shunt by a Fontan-type procedure can increase exercise tolerance by reducing arterial deoxygenation is not well documented. The cardiopulmonary exercise responses and the symptomatic status in two groups of univentricular patients, those who are cyanotic and those who are acyanotic with Fontan-type circulation, were compared. METHODS AND FINDINGS: Cardiopulmonary exercise testing was performed in 10 univentricular patients with rest or stress-induced cyanosis (age 30.5 +/- 2.3 [SE] years; 5 men) who had palliative or no surgery and eight patients (age 29.4 +/- 1.5 years; 4 men) with Fontan-type circulation. Peak oxygen consumption was comparable in both groups of univentricular patients (21.7 +/- 2.5 vs 21.0 +/- 1.9 ml.kg-1.min-1, P = 0.85) but was less than an age-matched group of 10 healthy subjects (34.7 +/- 1.9 ml.kg-1.min-1, P < 0.001 for both). Arterial oxygen saturation was 90.6% at rest in the cyanotic patients compared with 95.1% in the Fontan patients (P < 0.001) and at peak exercise, 66.2% compared with 90.5% (P < 0.001). Using a modified Borg scale (0-10), the symptoms of dyspnoea and fatigue were also assessed during exercise in the patient groups. The Borg scores for dyspnoea in the cyanotic and the corrected univentricular patients were, respectively, as follows: Stage 1: 0.5 vs 1.7; P= 0.04; Stage 2: 1.8 vs 2.3, P = 0.5; Stage 3: 3.0 vs 3.5, P = 0.7; Peak Exercise: 4.9 vs 4.8, P = 0.9. In addition, the Borg scores for fatigue were: Stage 1: 0.4 vs 1.6, P = 0.08; Stage 2: 2.0 vs 2.2, P = 0.9; Stage 3: 3.0 vs 4.3, P = 0.5; Peak Exercise: 4.9 vs 5.4, P = 0.5. The major limiting symptom at peak exercise was dyspnoea in four cyanotic patients compared with one in the Fontan group (Chi-square 0.982, P > 0.10). The arterial oxygen desaturation at peak exercise in the cyanotic patients limited by dyspnoea was not different from those limited by fatigue (67.5 +/- 10.1% vs 66.7 +/- 13.7%, P = 0.92). Exercise tolerance was also not related to the arterial oxygen saturation at peak exercise (r = 0.47, P = 0.17) in these patients. CONCLUSIONS: Despite correction with Fontan-type surgery, the exercise tolerance and symptoms of these univentricular patients remained similar to those who were cyanosed. Cyanotic patients have adjusted to chronic hypoxaemia and it does not appear to determine the exercise tolerance or the genesis of dyspnoea in these patients. Further randomized prospective studies are required to investigate the long-term benefits of Fontan-type procedures in these patients on exercise tolerance, symptoms and prognosis.     

Selection of medical treatment in stable angina pectoris: results of the International Multicenter Angina Exercise (IMAGE) Study

OBJECTIVES: The present study was designed to investigate which characteristics of anginal symptoms or exercise test results could predict the favorable anti-ischemic effect of the beta-adrenergic blocking agent metoprolol and the calcium antagonist nifedipine in patients with stable angina pectoris. BACKGROUND: The characteristics of anginal symptoms and the results of exercise testing are considered of great importance for selecting medical treatment in patients with chronic stable angina pectoris. However, little information is available on how this first evaluation may be used to select the best pharmacologic approach in individual patients. METHODS: In this prospective multicenter study, 280 patients with stable angina pectoris were enrolled in 25 European centers. After baseline evaluation, consisting of an exercise test and a questionnaire investigating patients' anginal symptoms, the patients were randomly allocated to double-blind treatment for 6 weeks with either metoprolol (Controlled Release, 200 mg once daily) or nifedipine (Retard, 20 mg twice daily) according to a parallel group design. At the end of this period, exercise tests were repeated 1 to 4 h after drug intake. RESULTS: Both metoprolol and nifedipine prolonged exercise tolerance over baseline levels; the improvement was greater in the patients receiving metoprolol (p < 0.05). Multivariate analysis revealed that low exercise tolerance was the only variable associated with a more favorable effect within each treatment group. Metoprolol was more effective than nifedipine in patients with a lower exercise tolerance or with a higher rate-pressure product at rest and at ischemic threshold. None of the characteristics of anginal symptoms or exercise test results predicted a greater efficacy of nifedipine over metoprolol. CONCLUSIONS: The results of a baseline exercise test, but not the characteristics of anginal symptoms, may offer useful information for selecting medical treatment in stable angina pectoris.     

The "muscle hypothesis" of chronic heart failure

Chronic heart failure is a well-recognized syndrome in which left ventricular impairment produces a constellation of secondary changes in other organ symptoms leading to symptoms such as muscular fatigue and dyspnoea and objective limitation to exercise tolerance. With modern drug therapy of diuretics and ACE inhibitors, the majority of patients have minimal if any signs of congestion, and yet severe symptomatic limitation remains. This limitation bears little relationship to conventional measures of either left ventricular function or the haemodynamic profile of the patient. The symptoms limiting exercise are predominantly fatigue or dyspnoea, and yet the classical pathophysiological explanations for their genesis now seem inadequate. Recent investigations, as demonstrated, in part, by the research presented in this symposium, attest to the importance of abnormalities in peripheral blood flow and in skeletal muscle in producing both objective limitation to exercise and in explaining the generation of the exercise-limiting symptoms of the syndrome of stable optimally treated chronic heart failure. In addition it is now evident that these muscle changes may in addition have pathophysiological significance for the maintenance of sympatho-excitation during exercise and potentially therefore in the progression of left ventricular remodelling and in the susceptibility to ventricular arrhythmias. This paper presents some of the background evidence which leads to the hypothesis that a feedback loop links changes in skeletal muscle to abnormal reflex cardiopulmonary control which may both limit exercise and be harmful in the progression of the syndrome.     

Computer-assisted measurement of lumbar spine radiographs

RATIONALE AND OBJECTIVES: The authors evaluated a method for obtaining reproducible, reliable measurements from standard lumbar spine radiographs for determining the degree of spondylolisthesis, vertebral body height, intervertebral disk space height, disk space angle, and degree of vertebral body wedging. MATERIALS AND METHODS: Four to six easily defined points were identified on each vertebral body on anteroposterior and lateral plain radiographs of the lumbosacral spine of patients. From these points, the degree of spondylolisthesis, the vertebral body height, the intervertebral disk space height, the disk space angle, and the degree of vertebral body wedging were easily calculated by using well-known geometric relationships. This method requires the use of a personal computer and a standard spreadsheet program but does not require the use of any other specialized radiographic equipment, computer hardware, or custom software. RESULTS: Calculations of intra- and interobserver variability for the measurement of spondylolisthesis, disk space height, disk space angle, and vertebral body height measurement showed that the technique is extremely reproducible. CONCLUSION: This technique may prove useful in the prospective evaluation of potential candidates for lumbar spinal stenosis surgery.     

Lifetime exercise and disk degeneration: an MRI study of monozygotic twins

Participation in some competitive sports has been shown to increase disk degeneration; however, the long-term effects of recreational physical activities are unclear. We investigated the effects of endurance exercise and power sports on disk degeneration in monozygotic male twins with contrasting lifetime exercise histories. The effects of endurance exercise were studied in 22 discordant twin pairs (mean lifetime frequencies of 3.9 vs 1.1 times/wk), and the effects of power sports were investigated in 12 discordant pairs (2,300 vs 200 h of weightlifting). The age range of the twins was from 35 to 69 yr. No differences in MRI findings between co-twins discordant for endurance exercise were found at any of the spinal regions. Subjects with more power sport involvement had greater disk degeneration in the T6-T12 region (P < 0.03), but similar findings were not present in the lumbar spine. Controlling for recalled back injuries, occupational loading, smoking, and driving did not significantly affect the results. No signs of beneficial or harmful effects of lifetime endurance exercise on disk degeneration were seen. Increased power sport participation was associated with slightly greater disk degeneration in the lower thoracic spine, but not in the lumbar spine.     

Isthmic spondylolisthesis in symptomatic and asymptomatic subjects, epidemiology, and natural history with special reference to disk abnormality and mode of treatment

Observations during the past 35 years on operative and conservative treatment of adult and young patients with isthmic spondylolisthesis, demonstrate the main indications of fusion are pain and risk of further progression of the slip. At one time, posterior fusion was recommended. Posterolateral fusion in situ was adopted in 1975, and during the past ten years anterior fusion combined with reduction and transpedicular fixation has been performed in severe slips. Surgery was mainly indicated to alleviate pain or to prevent further progression of the slip. It seems possible to alter the natural course of the disease by operation, but it is difficult to prove the connection between the radiographic findings and the pain. The epidemiologic study shows that the prevalence of spondylolisthesis in Finland is 6%, but there are no significant differences between these subjects and controls without spondylolisthesis. Symptomatic patients may have pain, however, even after a long observation time. Prevention of the slip is difficult because, statistically, 90% of the slip has already occurred when the patient is first seen. Posterolateral fusion in situ is the method of choice, especially for most young patients. Anterior fusion is indicated if the slip is greater than 40%-50%. Reduction of the slip is indicated in exceptional cases only.     

Effects of polyamines and calcium and sodium ions on smooth muscle cytoskeleton-associated phosphatidylinositol (4)-phosphate 5-kinase

Degenerative changes of the spinal column have long been and continue to be confused with the presence of spinal distress and pain. All parts of the spine undergo degenerative changes as we age. The purpose of this chapter is to describe the degenerative process and its clinical consequences. The disc degenerative process will be discussed; its consequences on the facet joint and osteophyte formation are considered. The prevalence of disc degeneration, the role of physically demanding work and leisure and the interference of spinal deformity is clarified. A section particularly important for the clinician deals with the clinical consequences of the degenerative process in disc herniation, degenerative spondylolisthesis, spondylolysis and stenosis. This chapter tries to put the degenerative changes of the spine into the context of a normal ageing process.     

Diabetes mellitus and sports

The adolescent with insulin-dependent diabetes mellitus (IDDM) can safely participate in sports activities without interference from the disease. To ensure safe and successful participation, clinicians must appreciate how diabetes may alter the physiologic adaptation to strenuous exercise and how an individualized self-care plan can empower the adolescent with IDDM to effectively manage meal planning, blood glucose testing, and insulin injections. Various types of insulin, insulin schedules, and insulin delivery devices that may suit a wide variety of training and activity regimens are described.     

Suppression of decorin expression and partial induction of anchorage-independent growth by the v-src oncogene in human fibroblasts

OBJECTIVE: To develop and test the intra-rater reliability of an interview-administered questionnaire that assesses lifetime patterns of total physical activity including occupational, household, and exercise/sports activities. METHODS: The questionnaire was developed and pretested using cognitive interviewing techniques on a sample of women with and without previous breast cancer diagnoses. A pilot study was conducted with 115 women who were interviewed twice, 6 to 8 wk apart by interviewers trained in cognitive interviewing methods. Respondents used recall calendars to record their education, occupations, life events, and physical activity patterns before the interviews. Interviewers helped respondents recall their lifetime exposures, including their occupational, household, and exercise/sports activities, using these calendars and memory-probing strategies. Activity levels were estimated as the average number of hours of activity per week over different time periods. Means and correlation coefficients were estimated and compared for the two time periods. RESULTS: The questionnaire was found to be highly reliable. The test-retest correlations for hours per week spent in total lifetime physical activity was 0.74, for lifetime occupational activity was 0.87, for household activity was 0.77, and for exercise/sports activities was 0.72. CONCLUSIONS: This is the first questionnaire to measure lifetime physical activity by collecting data on each type of physical activity separately over lifetime and by measuring frequency, intensity, and duration of each activity. It is also the first physical activity questionnaire to be developed, refined, and administered using cognitive-based methods employed in survey research. Respondents were able to reliably recall their lifetime physical activity patterns. This instrument can be used for any disease outcome for which physical activity may be a risk factor.     

Patterns of DSM-III-R alcohol dependence symptom progression in a general population survey

Age of onset reports obtained retrospectively for each symptom of DSM-III-R alcohol dependence (AD) are used to study patterns of lifetime symptom progression in a large general-population survey of people in the United States. It is shown that symptom progression among a substantial majority of respondents can be summarized as movement across three clusters. Cluster A is defined by symptoms of role impairment/hazardous use (A4), use despite social, psychological or physical problems (A6), and drinking larger amounts or over a longer period of time than intended (A1). Cluster B is defined by tolerance (A7) and impaired control (A2, A3). Cluster C is defined by withdrawal (A8, A9) and giving up activities in order to drink (A5). Clusters are shown to follow a time sequence, with at least one symptom in Cluster A usually occurring first, followed by symptoms in Clusters B and C. In all, 83.4% of the symptom cluster transitions estimated from retrospective age of onset reports are consistent with this progression. Progression to AD is differentially predicted by symptom profiles reported at the age of first symptom onset, with persons reporting Cluster C symptoms most likely to progress subsequently to AD. Furthermore, profiles of AD defined by the highest symptom cluster present at AD onset are differentially predicted by prior personal and parental histories of psychopathology and, among men, are predictive of diagnosis persistence.