Identifying Clinical and Paraclinical Predictors
Washington University in St. Louis
Advisor: Dr. Eugene Johnson
Supervisor: Dr. Tim Miller
Clinical heterogeneity in age-associated neurodegenerative disease presents diagnostic and therapeutic challenges for clinicians and researchers alike. Individual factors, including education, lifestyle (i.e., physical activity, diet), and comorbid medical conditions [i.e., heart disease, stroke] contribute to heterogeneity, and may represent potential targets for interventions aimed at modifying the course of disease. While many studies have considered the association between individual factors and specific causes of dementia, none have systematically considered their impact on rates of dementia progression. The proposed study will address this need by characterizing the clinical and paraclinical features associated with rates of progression in a large cohort of participants with dementia, with the goal of identifying measures that a) associate with rates of progression; and, b) predict final pathological diagnoses in participants with rapidly progressive, typically progressive and slowly-progressive disease.
Previous studies considering rates of progression have focused predominantly on rapidly progressive dementia due to prion diseases, limiting generalizability of findings. The RaPID Study will circumvent this limitation by considering rates of progression in participants recruited from an academic center focused on the diagnosis and management of age-associated neurodegenerative dementing diseases. Participants will be selected from >3100 participants, with and without dementia, recruited within the longitudinal Memory and Aging Project (MAP) at the Knight Alzheimer Disease Research Center at Washington University in St. Louis. Participants with dementia (Clinical Dementia Rating [CDR] ≥1) will be stratified by rates of progression according to intra-individual changes in CDR across assessments. The CDR is a widely used measure reflecting the stage of neurocognitive impairment; expected rates of change are established for MAP participants with Alzheimer dementia. Participants with rates of progression ≤2 standard deviations from that expected will be classified as “slowly progressive”. Participants with an increase of ≥2 CDR levels in ≤2 years or death within 5 years from dementia onset (resulting from the dementing illness) will be classified as rapidly progressive, yielding an estimated 118 participants. This sample will be further enriched by the retrospective inclusion of 54 patients with rapidly progressive dementia diagnosed and managed in the university-affiliated Memory and Diagnostic Center. Longitudinal clinical (history, physical examination, results of neuropsychological testing), paraclinical (genetics, cerebrospinal fluid, neuroimaging) and neuropathological findings will be compared within and between groups of participants.
This study will provide important information concerning the factors that influence rates of progression in dementia, and the etiologic causes of slowly, typically and rapidly progressive disease. This information may be adapted to improve clinical care by identifying secondary modifiers of disease that may be amenable to treatment, and providing more accurate information concerning disease prognosis in individuals. Additionally, these findings may be used to improve participant-selection for clinical research. Recent emphasis on the recruitment of minimally-symptomatic individuals for clinical trials has meant that participants must be followed for longer times to evaluate treatment effect. By increasing recruitment of individuals most likely to exhibit measurable cognitive/functional decline across the trial period, it may be possible to assess the treatment efficacy across shorter intervals, using smaller numbers of participants.
Few studies have considered the possibility that dementia syndromes commonly described as “slowly progressive” (i.e., Alzheimer disease; AD) may present as rapidly progressive dementia (RPD). To consider this, the RaPID Study sought to measure the prevalence and causes of RPD in older individuals in whom the risk of neurodegenerative disease is highest. Research records were reviewed from 1690 participants enrolled within a longitudinal study of memory and aging (Knight Alzheimer Disease Research Center at Washington University in St. Louis, St. Louis, Missouri), including 817 individuals with problems with memory and thinking. A novel criterion was applied to detect participants with faster-than expected progression of cognitive impairment. Using this method, 128 participants with RPD were identified (median age at diagnosis=79 [51-99) years; prevalence -8%). These participants were considered together with 54 patients diagnosed with RPD within the university-affiliated outpatient memory clinic (median age=69 [47-92) years).
AD dementia was the most common cause of RPD in both cohorts, accounting for 95% and 43% of research and clinical cases. Other causes of RPD included progressive posterior cortical dysfunction, dementia with Lewy bodies and frontotemporal dementia. Prion diseases (including Creutzfeldt-Jakob disease) were diagnosed in 3 (6%) patients (no research participants). Medical comorbidities were frequently encountered (most commonly depression, cerebrovascular disease and parkinsonism), and were especially prevalent in clinic patients with RPD attributed to AD dementia.
These results confirm that common causes of dementia can and frequently do present as RPD. Common neurodegenerative diseases (especially AD dementia) should be considered in older individuals with RPD. Evaluation should include screening for medical comorbidities, which may represent independent risk factors for dementia progression, and may respond to treatment. Work is continuing in the RaPID Study cohort to further elucidate the clinical features that can be detected early in the course of dementia and used to identify individuals at-risk for RPD.