Neuropsychiatric and cognitive factors predict progression to mild cognitive impairment and dementia

Poster Presentations: P2 Montreal, Quebec, Canada; 4McGill University, Montreal, Quebec, Canada. Contact e-mail: [email protected] Background: A new seven point scale for assessing the risk of mild cognitive impairment (MCI) and/or dementia is presented. The MCI Index is based on the two Cognistat subtests that are most sensitive to cognitive decline, Memory and Constructions, and it incorporates adjustments for age and education. It avoids the limitations of a single cutting score by providing a graded measure of the risk or probability that a patient with a particular set of scores suffers from either MCI or dementia. Methods: Although cognitive testing is highly sensitive to MCI, it cannot be used diagnostically apart from the clinical context, and the biomarkers sensitive to brain disease are typically negative early in the clinical course. The MCI Index avoids this dilemma by providing a risk assessment rather than a diagnosis. Index values are derived from a consideration of over a thousand combinations of scores and personal variables based on memory, constructional ability, age, level of education and language skill. These scores provide guidance to the clinicians who must then formulate the diagnosis within the context of their patient’s clinical history and presentation. Results: We present MCI Index data on thirteen patients (ages 60-88) previously evaluated with comprehensive neuropsychological testing. Eleven of the thirteen patients were judged to have either MCI or Alzheimer’s Disease based on history and the comprehensive test results. Ten of the eleven patients with prior diagnoses had MCI Index scores that ranged from 2 (suggests MCI) to 5 (suggests a dementia syndrome). The remaining patient, with an MCI Index score of 0, was an 88 year old man with minimal cognitive impairment that was rated as within normal limits for his age. Conclusions: MCI Index values range from 0 (no risk), through three levels of increasing risk for MCI (1 ¼ raises the question, 2 ¼ suggests, 3 ¼ strongly suggests MCI), to three levels of increasing risk for dementia (4 ¼ raises the question, 5 ¼ suggests, 6 ¼ strongly suggests a dementia syndrome). These values reflect increasing levels of cognitive impairment associated with an increasing risk for or likelihood of an MCI or dementia diagnosis.

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ASSOCIATING WECHSLER MEMORY SCALE LOGICAL MEMORY (LM) ERRORS AND CORRECT RESPONSES AND MRI REGIONS OF INTEREST FROM A HEALTHY COMMUNITYDWELLING COHORT: THE FRAMINGHAM HEART STUDY

David Libon1, Sarah Preis2, Alexa Beiser2, Sherral Devine2, Yulin Liu2, Sudha Seshadri3, Philip Wolf3, Au Rhoda2, 1Drexel University College of Medicine, Philadelphia, Pennsylvania, United States; 2Boston University, Boston, Massachusetts, United States; 3Boston University School of Medicine, Boston, Massachusetts, United States. Contact e-mail: dlibon@ drexelmed.edu Background: The Wechsler Memory Scale - Logical Memory subtest (LM) is commonly used to assess memory deficits in mild cognitive impairment (MCI) and dementia using conventional total recall scores. But LM also elicits errors that may reflect derailed cognitive domains not captured with standard scoring procedures. We tested hypotheses that additional scored responses undergoing principal component analysis will dissociate between LM correct responses, related errors, and unrelated errors reflecting different underlying memory and executive function processes; and, that associated MRI-regions of interest will be related to each of these three LM metrics. Methods: LM immediate (M+SE¼ 12.0+3.9) and delayed free recall (M+SE ¼ 10.9+4.1; and related (M+SE¼ 1.9 +1.0) and unrelated (M+SE¼ 0.1+ 0.4) errors were obtained from 1,954 Framingham Offspring Cohort participants (M+SE age¼ 67.3+9.1; percent female¼ 54.4) and subjected to a principal component analysis. The analysis yielded three factors: correct responses (factor 1), unrelated errors (factor 2), and related errors (factor 3). Volumetric MRI measures of total brain, frontal lobe, temporal horn, and white matter hyperintensities were available for 1,564 participants. Results: Regression analyses controlling for age, sex, and education found higher immediate/ delayed free recall (factor 1) was associated with reduced temporal horn volume (beta¼ -0.066+0.024, p¼ 0.007). This rela-

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tionship remained significant after further adjustment for cardiovascular risk/ APOE 4 allele (beta¼ -0.055+0.025, p¼ 0.03). Higher numbers of unrelated errors (factor 2) were associated with more white matter hyperintensities (beta¼ 0.048+0.025; p¼ 0.05); and smaller frontal lobe volume (beta¼ -0.056+0.027, p¼ 0.04). These relationships were not significant after controlling for cardiovascular risk/ APOE 4 allele. No relationship between LM related errors and MRI-regions of interest were found. Conclusions: In this healthy community-based sample, the base rate for LM errors was small. Nonetheless, consistent with research using verbal serial-list learning tests, these data suggest differ brain behavior relationships underlie LM correct responses and unrelated errors. When LM errors occur in greater frequency, despite normal immediate and delay free recall test scores, underlying executive functions deficits may be present. These data should be validated with MCI and dementia patients to further assess clinical utility.

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NEUROPSYCHIATRIC AND COGNITIVE FACTORS PREDICT PROGRESSION TO MILD COGNITIVE IMPAIRMENT AND DEMENTIA

Nancy Donovan1, Amy Zoller2, Rebecca Rudel2, Rebecca Amariglio2, Joseph Locascio3, Keith Johnson3, Reisa Sperling4, Gad Marshall4, Dorene Rentz4, 1Brigham and Women’s Hospital/ Center for Alzheimer Research and Treatment, Boston, Massachusetts, United States; 2 Massachusetts General Hospital, Charlestown, Massachusetts, United States; 3Massachusetts General Hospital, Boston, Massachusetts, United States; 4Brigham and Women’s Hospital, Boston, Massachusetts, United States. Contact e-mail: [email protected] Background: Identifying factors that predict progression in clinically normal (CN) older individuals to Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD) is essential as the field moves toward early prevention trials. Prior studies suggest that subjective cognitive concerns (SCC), neuropsychiatric symptoms and lower performance on select neuropsychological tests may individually serve as markers of impending cognitive decline in CN elderly prior to the diagnosis of MCI. Methods: Five hundred and sixty subjects participating in the Massachusetts Alzheimer’s Disease Research Center longitudinal cohort (157 MCI, 344 CN, 59 SCC) underwent assessments at baseline and annually (mean follow-up¼2 years, range¼1-5) including the Unified Dataset neuropsychological battery and the Neuropsychiatric Inventory brief questionnaire (NPI-Q). Separate analysis of these measures yielded two cognitive factors defined as "Memory/ Semantic" and "Attention/Executive" and two neuropsychiatric factors categorized as "Affective" (consisting of NPI-Q items depression, irritability, agitation, disinhibition, anxiety, apathy) and "Psychotic" (hallucinations, aberrant motor behaviors, night-time behaviors, appetite disturbance, delusions). Cognitive and Neuropsychiatric factors were analyzed as predictors of time to progression to a worse diagnosis using a Cox proportional hazards regression model with backward elimination. Covariates included age, education, prior depression, antidepressant medication use, symptom duration, diagnosis and the interaction of each neuropsychiatric factor with diagnosis. Results: Baseline diagnosis (p¼0.004), Memory/Semantic factor (p<0.0001) and Affective factor (p¼0.02) were individually significant predictors of progression to a worse diagnosis over time. There was a higher hazard rate of progression in the SCC group compared to both CN (p<0.01, HR¼2.5, 95% CI for HR¼1.4,4.4) and MCI groups (p<0.01; HR¼2.4, 95% CI for HR¼1.3,4.6), but no significant difference in hazard rate of progression between CN and MCI groups. Greater (better) Memory/Semantic factor scores predicted less hazard of progression (HR¼0.4 for one SD increase; 95% CI for HR¼0.3,0.6), and a higher (worse) Affective factor score predicted greater hazard (HR¼1.3 for one SD increase; 95% CI for HR¼1.0,1.5). Interaction terms were not significant predictors of progression. Conclusions: These results identify select neuropsychological and neuropsychiatric factors associated with disease progression across early stages of cognitive decline and highlight the subgroup of cognitively normal elderly with subjective cognitive concerns as those with high risk for progression to MCI.