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Empirically derived mild cognitive impairment subtypes based on performance on memory tests predict conversion to Alzheimer's disease
S242
Poster Presentations P1
(SD4.80), (CDR3) M ¼ 3.57 (SD3.56). Results: Subjects cognitively healthy (N ¼ 40; 35.40%) met the inclusion criteria for the ControlGroup. However patients with (AD) showed a tendency to cognitive decline [(MMSE), (CDR 0)M ¼ 28.57 (SD1.46); (CDR 1) M ¼ 22.65 (SD4.91); (CDR 2) M13.62 (SD7,24); (CDR 3) M ¼ 5.85 (SD4.32)], dependency in activities of daily live [(Katz) (CDR 0) M ¼ .05 (SD.22); (CDR 1) M ¼ 10.05 (SD8.64); M ¼ 27.25 (SD7.91); M ¼ 37.21 (SD4.20)], decrease of functional stage [(FAST) (CDR 0) M ¼ .07 (SD .26); (CDR 1) M ¼ 4.4 (SD1.41); (CDR2)M ¼ 5.5 (SD1,31); (CDR3) M ¼ 6.71 (SD .46)] and evidence of non-Piagetian conservation, so match the severity of the disease in three stages (CDR). Conclusions: This study confirms previous findings that in AD, cognitive decline has characteristics similar to the Piaget theoretical model, but in a reverse development pattern (retrogenesis). P1-405
EMPIRICALLY DERIVED MILD COGNITIVE IMPAIRMENT SUBTYPES BASED ON PERFORMANCE ON MEMORY TESTS PREDICT CONVERSION TO ALZHEIMER’S DISEASE
Maritza Dowling1, Shubhabrata Mukherjee2, Jodi Casabianca3, Cathy LaBrish4, 1University of Wisconsin-Madison, Madison, Wisconsin, United States; 2University of Washington, Seattle, Seattle, Washington, United States; 3Fordham University, New York City, New York, United States; 4York University, Toronto, Ontario, Ontario, Canada. Background: Diagnostic accuracy, particularly for early-onset Alzheimer’s and other dementias, presents a number of challenges that often prevent timely intervention and treatment therapies to slow disease progression. The use of neuropsychological tests for the assessment of cognitive function is a core part of the diagnosis protocol. Evidently, the higher the sensitivity, specificity, and robustness of the tests selected to measure cognitive dysfunction, the more effectively such testing can be used as biomarkers for early diagnosis along with other essential biomarkers to support a preclinical syndrome of dementia. Mild cognitive impairment refers to an early stage or transitional period between normal aging and AD (Mueller, Schuff, & Weiner, 2006). The concept, however, has been operationalized in many different ways using inconsistent criteria and the long-term outcomes of the diagnosis are often mixed. Several subtypes of MCI have been identified according to the cognitive domain affected. Among these subtypes, amnestic MCI, is considered a risk state for the development of AD and is defined as impairment on a memory test and a subjective memory complaint, but preserved general cognitive functioning (Petersen et al., 1999). Early diagnosis to provide appropriate treatment and intervention requires accurate criteria for the identification and profiling of individuals at risk to progress to AD. Another challenge in the identification of risk groups based on neuropsychological test outcomes that reflect underlying pathology is the lack of uniformity in the selection of cognitive measures and norms making it difficult to compare results across studies. This study applied a latent profile analysis, a person-centered approach, to construct a quantitative typology of amnestic MCI individuals based on response profiles in a comprehensive unidimensional set of memory scales administered at baseline. The effect of latent subgroup membership on conversion from MCI to AD in a 24-month period was examined as well as cerebrospinal (CSF) fluid level differences across groups. We further examined the association between latent group membership and brain atrophy levels in a 24-month period. Methods: The study included 397 individuals from the Alzheimer’s Disease Neuroimage Initiative (ADNI; www.loni.ucla.edu/ADNI) study who were diagnosed as MCI at baseline and had complete data on the neuropsychological scales measuring the memory construct. The sample ranged in age from 55 to 90 (M ¼ 74.8, S.D. ¼ 7.46), with a mean education level of 16 years, and a gender composition of 64% male. The dimensionality of all the tests was examined first through a multi-step iterative process using structural equation modeling. A series of competing models were developed and compared. The components of the model producing the best fitting unidimensional model were used as indicators in the latent profile model. Interpretability and theoretical significance were also taken into account
in the selection of the final model. Fourteen different components or “subscales” from the following three tests remained as observed indicators: the Rey Auditory Verbal Learning Test (AVLT; Rey, 1964), the Alzheimer’s Disease Assessment Scale (ADAS-Cog; Rosen, Mohs, & Davis, 1984), and the Wechsler Memory Scale-3rd ed., Logical Memory (LM) subtest (Wechsler, 1997). The plausibility of the unconditional 1-, 2-, and 3-latent class solutions was investigated first. Classes were added iteratively and models were compared by examining multiple fit criteria and overall model interpretability. Once the best-fitting solution was selected, we added predictors of class membership to the model and a distal outcome. That is, to describe the heterogeneity of the latent classes or “typologies” and explain differences across classes, we modeled conversion to AD in a 24-month period as a distal outcome to examine the long-term effects of different typologies. Apolipoprotein E (APOE) e4 allele status, gender, education, and age were added as covariates to increase the accuracy of the classification and study correlates of class membership. All model parameters were estimated simultaneously using direct maximum likelihood to handle missing data. A second step in the analysis was to validate the model-implied solution by examining the relationship between CSF bio marker levels, total tau (t-tau), phosphorylated tau(p-tau 181), and beta-amyloid 42 (Ap42) across latent amnestic MCI subgroups. Finallywe used multivariate tensor-based morphometry to compare across mixture components or latent classes and study how these subtypes/latent classes predicted brain atrophy in a 24-month period. Results: The iterative modeling approach produced a best-fitting model with two subgroups or latent classes with over 90% classification accuracy. APOE and education were significant predictors of class membership for the “low memory performance” class. This class had a higher proportion of APOE4’s (odds ratio ¼ 2.65) and lower education level (odds ratio - 0.87). About 50% of the baseline amnestic MCI individuals in the “low memory performance class”; converted to AD in 24 months (p < 0.001) while only 7.7% converted to AD in the “High memory” performance class (p¼0.013). Consistent with prior research, the “low memory” performance class also had significantly lower CSF-Ap42 levels at baseline and higher t-tauand p-tau CSF levels compared to the “high memory” performance latent class. As expected atrophy rates were significantly higher in the “lower performance” latent group. Conclusions: Amnestic MCI is not a homogeneous disease state (or subtype) classification. Results of a latent profile model showed two distinct subgroups of amnestic MCI individuals. Furthermore, rates of conversion to AD may vary considerably even within traditional MCI subtype classifications. It should be noted that not all the memory subscales have the same sensitivity to discriminate between MCI subtypes. This may affect their utility for screening and tracking disease. A strategy to improve clinical study design is the enrichment of the study population by restricting participation or eligibility to an “enriched” population identified by measures sensitive enough to detect those with a higher likelihood of conversion to AD. Targeting subgroups of amnestic MCI according to specific profiles of memory performance may be a promising strategy to track the progression of the disease and increase the effectiveness of intervention therapies.
P1-406
VISUO-PERCEPTUAL TASK PERFORMANCE IN DEMENTIA WITH LEWY BODIES
Christopher Edgar, Keith Wesnes, United BioSource Corporation, Goring-on-Thames, United Kingdom. Background: Dementia with Lewy Bodies (DLB) is a common form of dementia. The profile of cognitive impairment shows relatively greater impairment to visuospatial ability, attention and executive function versus memory when compared to Alzheimer’s disease (AD). Thus the exploration of domain specific aspects of cognition in DLB patients is of interest. A computerized visuo-perceptual task battery previously demonstrated discriminant validity, showing a marked impairment in both DLB and Parkinson disease dementia (PDD) versus AD, PD and normal controls. However, basic psychometric properties were not explored. Methods: This was a multicenter, investigator-initiated, open-label, flexible-dose (8-24 mg/day), 24-week study of galantamine in 50 patients with mild to moderately severe DLB. Mean age was 76.5 years (range 50 to 91). There were 29 male and 21
Poster Presentations P1
(SD4.80), (CDR3) M ¼ 3.57 (SD3.56). Results: Subjects cognitively healthy (N ¼ 40; 35.40%) met the inclusion criteria for the ControlGroup. However patients with (AD) showed a tendency to cognitive decline [(MMSE), (CDR 0)M ¼ 28.57 (SD1.46); (CDR 1) M ¼ 22.65 (SD4.91); (CDR 2) M13.62 (SD7,24); (CDR 3) M ¼ 5.85 (SD4.32)], dependency in activities of daily live [(Katz) (CDR 0) M ¼ .05 (SD.22); (CDR 1) M ¼ 10.05 (SD8.64); M ¼ 27.25 (SD7.91); M ¼ 37.21 (SD4.20)], decrease of functional stage [(FAST) (CDR 0) M ¼ .07 (SD .26); (CDR 1) M ¼ 4.4 (SD1.41); (CDR2)M ¼ 5.5 (SD1,31); (CDR3) M ¼ 6.71 (SD .46)] and evidence of non-Piagetian conservation, so match the severity of the disease in three stages (CDR). Conclusions: This study confirms previous findings that in AD, cognitive decline has characteristics similar to the Piaget theoretical model, but in a reverse development pattern (retrogenesis). P1-405
EMPIRICALLY DERIVED MILD COGNITIVE IMPAIRMENT SUBTYPES BASED ON PERFORMANCE ON MEMORY TESTS PREDICT CONVERSION TO ALZHEIMER’S DISEASE
Maritza Dowling1, Shubhabrata Mukherjee2, Jodi Casabianca3, Cathy LaBrish4, 1University of Wisconsin-Madison, Madison, Wisconsin, United States; 2University of Washington, Seattle, Seattle, Washington, United States; 3Fordham University, New York City, New York, United States; 4York University, Toronto, Ontario, Ontario, Canada. Background: Diagnostic accuracy, particularly for early-onset Alzheimer’s and other dementias, presents a number of challenges that often prevent timely intervention and treatment therapies to slow disease progression. The use of neuropsychological tests for the assessment of cognitive function is a core part of the diagnosis protocol. Evidently, the higher the sensitivity, specificity, and robustness of the tests selected to measure cognitive dysfunction, the more effectively such testing can be used as biomarkers for early diagnosis along with other essential biomarkers to support a preclinical syndrome of dementia. Mild cognitive impairment refers to an early stage or transitional period between normal aging and AD (Mueller, Schuff, & Weiner, 2006). The concept, however, has been operationalized in many different ways using inconsistent criteria and the long-term outcomes of the diagnosis are often mixed. Several subtypes of MCI have been identified according to the cognitive domain affected. Among these subtypes, amnestic MCI, is considered a risk state for the development of AD and is defined as impairment on a memory test and a subjective memory complaint, but preserved general cognitive functioning (Petersen et al., 1999). Early diagnosis to provide appropriate treatment and intervention requires accurate criteria for the identification and profiling of individuals at risk to progress to AD. Another challenge in the identification of risk groups based on neuropsychological test outcomes that reflect underlying pathology is the lack of uniformity in the selection of cognitive measures and norms making it difficult to compare results across studies. This study applied a latent profile analysis, a person-centered approach, to construct a quantitative typology of amnestic MCI individuals based on response profiles in a comprehensive unidimensional set of memory scales administered at baseline. The effect of latent subgroup membership on conversion from MCI to AD in a 24-month period was examined as well as cerebrospinal (CSF) fluid level differences across groups. We further examined the association between latent group membership and brain atrophy levels in a 24-month period. Methods: The study included 397 individuals from the Alzheimer’s Disease Neuroimage Initiative (ADNI; www.loni.ucla.edu/ADNI) study who were diagnosed as MCI at baseline and had complete data on the neuropsychological scales measuring the memory construct. The sample ranged in age from 55 to 90 (M ¼ 74.8, S.D. ¼ 7.46), with a mean education level of 16 years, and a gender composition of 64% male. The dimensionality of all the tests was examined first through a multi-step iterative process using structural equation modeling. A series of competing models were developed and compared. The components of the model producing the best fitting unidimensional model were used as indicators in the latent profile model. Interpretability and theoretical significance were also taken into account
in the selection of the final model. Fourteen different components or “subscales” from the following three tests remained as observed indicators: the Rey Auditory Verbal Learning Test (AVLT; Rey, 1964), the Alzheimer’s Disease Assessment Scale (ADAS-Cog; Rosen, Mohs, & Davis, 1984), and the Wechsler Memory Scale-3rd ed., Logical Memory (LM) subtest (Wechsler, 1997). The plausibility of the unconditional 1-, 2-, and 3-latent class solutions was investigated first. Classes were added iteratively and models were compared by examining multiple fit criteria and overall model interpretability. Once the best-fitting solution was selected, we added predictors of class membership to the model and a distal outcome. That is, to describe the heterogeneity of the latent classes or “typologies” and explain differences across classes, we modeled conversion to AD in a 24-month period as a distal outcome to examine the long-term effects of different typologies. Apolipoprotein E (APOE) e4 allele status, gender, education, and age were added as covariates to increase the accuracy of the classification and study correlates of class membership. All model parameters were estimated simultaneously using direct maximum likelihood to handle missing data. A second step in the analysis was to validate the model-implied solution by examining the relationship between CSF bio marker levels, total tau (t-tau), phosphorylated tau(p-tau 181), and beta-amyloid 42 (Ap42) across latent amnestic MCI subgroups. Finallywe used multivariate tensor-based morphometry to compare across mixture components or latent classes and study how these subtypes/latent classes predicted brain atrophy in a 24-month period. Results: The iterative modeling approach produced a best-fitting model with two subgroups or latent classes with over 90% classification accuracy. APOE and education were significant predictors of class membership for the “low memory performance” class. This class had a higher proportion of APOE4’s (odds ratio ¼ 2.65) and lower education level (odds ratio - 0.87). About 50% of the baseline amnestic MCI individuals in the “low memory performance class”; converted to AD in 24 months (p < 0.001) while only 7.7% converted to AD in the “High memory” performance class (p¼0.013). Consistent with prior research, the “low memory” performance class also had significantly lower CSF-Ap42 levels at baseline and higher t-tauand p-tau CSF levels compared to the “high memory” performance latent class. As expected atrophy rates were significantly higher in the “lower performance” latent group. Conclusions: Amnestic MCI is not a homogeneous disease state (or subtype) classification. Results of a latent profile model showed two distinct subgroups of amnestic MCI individuals. Furthermore, rates of conversion to AD may vary considerably even within traditional MCI subtype classifications. It should be noted that not all the memory subscales have the same sensitivity to discriminate between MCI subtypes. This may affect their utility for screening and tracking disease. A strategy to improve clinical study design is the enrichment of the study population by restricting participation or eligibility to an “enriched” population identified by measures sensitive enough to detect those with a higher likelihood of conversion to AD. Targeting subgroups of amnestic MCI according to specific profiles of memory performance may be a promising strategy to track the progression of the disease and increase the effectiveness of intervention therapies.
P1-406
VISUO-PERCEPTUAL TASK PERFORMANCE IN DEMENTIA WITH LEWY BODIES
Christopher Edgar, Keith Wesnes, United BioSource Corporation, Goring-on-Thames, United Kingdom. Background: Dementia with Lewy Bodies (DLB) is a common form of dementia. The profile of cognitive impairment shows relatively greater impairment to visuospatial ability, attention and executive function versus memory when compared to Alzheimer’s disease (AD). Thus the exploration of domain specific aspects of cognition in DLB patients is of interest. A computerized visuo-perceptual task battery previously demonstrated discriminant validity, showing a marked impairment in both DLB and Parkinson disease dementia (PDD) versus AD, PD and normal controls. However, basic psychometric properties were not explored. Methods: This was a multicenter, investigator-initiated, open-label, flexible-dose (8-24 mg/day), 24-week study of galantamine in 50 patients with mild to moderately severe DLB. Mean age was 76.5 years (range 50 to 91). There were 29 male and 21