- Email: [email protected]
CSF biomarkers and APOE genotype as predictors of clinical progression in patients with subjective complaints
P824
Featured Research Sessions: F5-01: Subjective Cognitive Decline in Preclinical Alzheimer’s Disease
FEATURED RESEARCH SESSIONS: F5-01: SUBJECTIVE COGNITIVE DECLINE IN PRECLINICAL ALZHEIMER’S DISEASE F5-01-01
A CONCEPTUAL FRAMEWORK OF SUBJECTIVE COGNITIVE DECLINE (SCD) IN PRECLINICAL ALZHEIMER’S DISEASE (AD)
Frank Jessen, University of Bonn, Bonn, Germany. Contact e-mail: frank. [email protected] Background: Biomarker-based early recognition research in AD is moving to the preclinical stage. One challenge is identifying individuals, which are at increased risk of having preclinical AD and of progressing to dementia. Growing evidence suggest that the self-experienced decline in cognitive performance in elderly subjects with otherwise normal performance on cognitive tests (subjective cognitive decline, SCD) is a risk factor for future AD dementia and indicates an increased likelihood for the presence of preclinical AD in individuals. A major limitation for further refinement of SCD as an indicator of preclinical AD is the lack of a common framework and common research standards on this topic. Methods: In November 2012 the SCD-Initiative (SCD-I) was founded to develop a common framework on the research on SCD in preclinical AD. The working group includes main authors of the recently presented criteria of preclinical AD, MCI due AD and prodromal AD as well a main investigators of prominent biomarker initiatives (ADNI, AIBL, DESCRIPA, Dementia Competence Network) and large population-based cohort studies. In a number of e-mail discussions the common research framework was developed. Results: The group concludes that the currently available data is too limited and too heterogeneous to define SCD in preclinical AD as a clear-cut entity and highlights the need for intensified research on this topic. The SCD-I created a research framework which defines terminology and provides guidance on the coding of on key features of SCD in research projects. Thus, it allows the integration of a wide variety of research approaches in different settings and cohorts and achieves comparability across different studies. The core components of the framework will be presented in the session. Conclusions: The research framework sets the stage for intensified and comparable research on SCD in preclinical AD. It provides the basis to investigate characteristics and dynamics of the earliest symptomatic stage of AD and to eventually evaluate the usefulness of SCD as a clinical sign of the biomarker based diagnosis of preclinical AD. F5-01-02
CSF BIOMARKERS AND APOE GENOTYPE AS PREDICTORS OF CLINICAL PROGRESSION IN PATIENTS WITH SUBJECTIVE COMPLAINTS
Wiesje Van der Flier, VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: [email protected] Background: We investigated the independent and combined predictive value of CSF biomarkers and APOE genotype for clinical progression in patients with subjective complaints. Methods: We included 229 patients with subjective complaints (6169 yrs; 93(41%) F; MMSE 2862) from our memory clinic based Amsterdam Dementia Cohort. Patients were eligible when CSF biomarkers, APOE genotype and follow-up (m6sd; 362yrs) were available. After follow-up, 192 patients remained stable, 21 progressed to MCI and 8 developed AD. Five patients progressing to non-AD dementia were not included in further analyses. Clinical progression was defined as patients progressing to MCI or AD. Predictive value of dichotomized CSF biomarkers and APOE genotype were assessed using Cox proportional hazard models adjusted for age, sex and MMSE. Results: Patients showing clinical progression (n¼29(13%)) were older than patients who remained stable. There were no differences in sex or MMSE. They were more often APOE e4 carrier (62% vs 38%; p<0.05). CSF levels were lower in patients who showed clinical progression for ab42 and higher for (p)tau (ab42 6396290 vs 8646227; tau 4506253 vs 2776191; ptau 66631vs 48621; all p<0.01). Overall, APOE e4 carriers had lower ab42 and higher (p)tau than APOE e4 non-carriers (all p<0.05). APOE e4carriers had a more than twofold increased risk of clinical progression (HR (95% CI): 2.2 (1.0-4.8)).
For the CSF biomarkers, abnormal ab42 was associated with the highest increased risk (HR (95% CI): 6.6 (3.0-14.6)), followed by tau (4.3 (1.9-9.8)) and ptau (2.8 (1.3-6.4)). There was a significant interaction between APOE genotype and CSF ab42 (p<0.05), but not between APOE genotype and CSF tau or ptau. After stratification for APOE, CSF ab42 had the strongest predictive value in APOE e4 noncarriers (HR (95% CI): 35 (6-217)), while the predictive value in APOE e4 carriers was modest (3.1 (1.1-8.4)). Conclusions: In patients with subjective complaints, a subset of which has preclinical AD, CSF ab42 is the strongest predictor of clinical progression, especially in APOE e4 noncarriers. This finding illustrates that the effect of betaamyloid 42 at least partially follows a different, not APOE-related pathway. F5-01-03
NEUROPSYCHOLOGICAL AND NEUROIMAGING DIFFERENCES BETWEEN INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE RECRUITED FROM MEMORY CLINIC VERSUS FROM THE GENERAL POPULATION
Audrey Perrotin, Inserm - EPHE - UCBN U1077, Caen, France. Contact e-mail: [email protected] Background: Subjective cognitive decline (SCD) may be the first clinical sign of Alzheimer disease (AD). A recent initiative aimed at further defining the SCD concept in relation to preclinical AD. Within this framework, the objective of the present study was to assess the relevance of the setting in selecting SCD individuals with high likelihood to develop AD. Methods: A total of 51 elderly without objective cognitive deficits were included in the study, on which 10 were recruited from a memory clinic (SCD-clinic), 21 were elderly from the general population with a high self-rating on the “MacNair” Cognitive Difficulties Scale (SCD-population), and 20 were controls with low rating on the MacNair. Data from detailed neuropsychological assessment, structuralMRI, FDG-PETand amyloid Florbetapir-PETwere acquired and compared between groups. Results: No significant difference was found between the three groups regarding demography and ApoE4 genotyping. As expected, both SCDclinic and SCD-population showed higher self- and informant-ratings on the MacNair compared to the controls, but the two groups didn’t differ from one another. No difference was found in any neuropsychological test between the three groups. Regarding neuroimaging biomarkers, highly significant differences were found in the SCD-clinic compared to controls or SCD-population in the hippocampal region, including both gray matter atrophy and hypometabolism. By contrast, the SCI-population didn’t show any significant difference compared to controls but their MacNair rating tended to positively correlate with atrophy, including (but not only) within the hippocampal region. SCD was related with Florbetapir-PET measurement in the frontal cortex but this effect cancelled when controlling for ApoE4 genotype. Conclusions: Our findings showed that, among two SCD groups without objective deficits and same degree of subjective cognitive decline, only those who seek help for memory concern showed significant atrophy, with a topography consistent with early AD. In line with studies showing that worries associated with SCD increase the risk for AD, these findings highlight the relevance of memory clinic setting in selecting SCD with a high likelihood of developing AD. The degree of subjective cognitive decline in the general population may also be relevant but is probably associated to a more heterogeneous outcome. F5-01-04
SUBJECTIVE COGNITIVE CONCERNS AS AN EARLY INDICATOR OF ALZHEIMER’S DISEASE PATHOLOGY
Rebecca Amariglio, Massachusetts General Hospital, Boston, Massachusetts, United States. Contact e-mail: RAMARIGLIO@partners. org Background: Although self-reported cognitive concerns (SCC) have previously been dismissed as a sign of the “worried well”, there is emerging evidence to suggest that SCC may herald initial cognitive decrements at the stage of preclinical Alzheimer’s disease (AD). Recent preliminary data from our own group and others suggests that specific SCC may in fact indicate early awareness prior to objective impairment on standardized tests and may be associated with evidence of early pathology on AD biomarkers. Methods: Multimodality studies relating SCC with AD biomarker evidence
Featured Research Sessions: F5-01: Subjective Cognitive Decline in Preclinical Alzheimer’s Disease
FEATURED RESEARCH SESSIONS: F5-01: SUBJECTIVE COGNITIVE DECLINE IN PRECLINICAL ALZHEIMER’S DISEASE F5-01-01
A CONCEPTUAL FRAMEWORK OF SUBJECTIVE COGNITIVE DECLINE (SCD) IN PRECLINICAL ALZHEIMER’S DISEASE (AD)
Frank Jessen, University of Bonn, Bonn, Germany. Contact e-mail: frank. [email protected] Background: Biomarker-based early recognition research in AD is moving to the preclinical stage. One challenge is identifying individuals, which are at increased risk of having preclinical AD and of progressing to dementia. Growing evidence suggest that the self-experienced decline in cognitive performance in elderly subjects with otherwise normal performance on cognitive tests (subjective cognitive decline, SCD) is a risk factor for future AD dementia and indicates an increased likelihood for the presence of preclinical AD in individuals. A major limitation for further refinement of SCD as an indicator of preclinical AD is the lack of a common framework and common research standards on this topic. Methods: In November 2012 the SCD-Initiative (SCD-I) was founded to develop a common framework on the research on SCD in preclinical AD. The working group includes main authors of the recently presented criteria of preclinical AD, MCI due AD and prodromal AD as well a main investigators of prominent biomarker initiatives (ADNI, AIBL, DESCRIPA, Dementia Competence Network) and large population-based cohort studies. In a number of e-mail discussions the common research framework was developed. Results: The group concludes that the currently available data is too limited and too heterogeneous to define SCD in preclinical AD as a clear-cut entity and highlights the need for intensified research on this topic. The SCD-I created a research framework which defines terminology and provides guidance on the coding of on key features of SCD in research projects. Thus, it allows the integration of a wide variety of research approaches in different settings and cohorts and achieves comparability across different studies. The core components of the framework will be presented in the session. Conclusions: The research framework sets the stage for intensified and comparable research on SCD in preclinical AD. It provides the basis to investigate characteristics and dynamics of the earliest symptomatic stage of AD and to eventually evaluate the usefulness of SCD as a clinical sign of the biomarker based diagnosis of preclinical AD. F5-01-02
CSF BIOMARKERS AND APOE GENOTYPE AS PREDICTORS OF CLINICAL PROGRESSION IN PATIENTS WITH SUBJECTIVE COMPLAINTS
Wiesje Van der Flier, VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: [email protected] Background: We investigated the independent and combined predictive value of CSF biomarkers and APOE genotype for clinical progression in patients with subjective complaints. Methods: We included 229 patients with subjective complaints (6169 yrs; 93(41%) F; MMSE 2862) from our memory clinic based Amsterdam Dementia Cohort. Patients were eligible when CSF biomarkers, APOE genotype and follow-up (m6sd; 362yrs) were available. After follow-up, 192 patients remained stable, 21 progressed to MCI and 8 developed AD. Five patients progressing to non-AD dementia were not included in further analyses. Clinical progression was defined as patients progressing to MCI or AD. Predictive value of dichotomized CSF biomarkers and APOE genotype were assessed using Cox proportional hazard models adjusted for age, sex and MMSE. Results: Patients showing clinical progression (n¼29(13%)) were older than patients who remained stable. There were no differences in sex or MMSE. They were more often APOE e4 carrier (62% vs 38%; p<0.05). CSF levels were lower in patients who showed clinical progression for ab42 and higher for (p)tau (ab42 6396290 vs 8646227; tau 4506253 vs 2776191; ptau 66631vs 48621; all p<0.01). Overall, APOE e4 carriers had lower ab42 and higher (p)tau than APOE e4 non-carriers (all p<0.05). APOE e4carriers had a more than twofold increased risk of clinical progression (HR (95% CI): 2.2 (1.0-4.8)).
For the CSF biomarkers, abnormal ab42 was associated with the highest increased risk (HR (95% CI): 6.6 (3.0-14.6)), followed by tau (4.3 (1.9-9.8)) and ptau (2.8 (1.3-6.4)). There was a significant interaction between APOE genotype and CSF ab42 (p<0.05), but not between APOE genotype and CSF tau or ptau. After stratification for APOE, CSF ab42 had the strongest predictive value in APOE e4 noncarriers (HR (95% CI): 35 (6-217)), while the predictive value in APOE e4 carriers was modest (3.1 (1.1-8.4)). Conclusions: In patients with subjective complaints, a subset of which has preclinical AD, CSF ab42 is the strongest predictor of clinical progression, especially in APOE e4 noncarriers. This finding illustrates that the effect of betaamyloid 42 at least partially follows a different, not APOE-related pathway. F5-01-03
NEUROPSYCHOLOGICAL AND NEUROIMAGING DIFFERENCES BETWEEN INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE RECRUITED FROM MEMORY CLINIC VERSUS FROM THE GENERAL POPULATION
Audrey Perrotin, Inserm - EPHE - UCBN U1077, Caen, France. Contact e-mail: [email protected] Background: Subjective cognitive decline (SCD) may be the first clinical sign of Alzheimer disease (AD). A recent initiative aimed at further defining the SCD concept in relation to preclinical AD. Within this framework, the objective of the present study was to assess the relevance of the setting in selecting SCD individuals with high likelihood to develop AD. Methods: A total of 51 elderly without objective cognitive deficits were included in the study, on which 10 were recruited from a memory clinic (SCD-clinic), 21 were elderly from the general population with a high self-rating on the “MacNair” Cognitive Difficulties Scale (SCD-population), and 20 were controls with low rating on the MacNair. Data from detailed neuropsychological assessment, structuralMRI, FDG-PETand amyloid Florbetapir-PETwere acquired and compared between groups. Results: No significant difference was found between the three groups regarding demography and ApoE4 genotyping. As expected, both SCDclinic and SCD-population showed higher self- and informant-ratings on the MacNair compared to the controls, but the two groups didn’t differ from one another. No difference was found in any neuropsychological test between the three groups. Regarding neuroimaging biomarkers, highly significant differences were found in the SCD-clinic compared to controls or SCD-population in the hippocampal region, including both gray matter atrophy and hypometabolism. By contrast, the SCI-population didn’t show any significant difference compared to controls but their MacNair rating tended to positively correlate with atrophy, including (but not only) within the hippocampal region. SCD was related with Florbetapir-PET measurement in the frontal cortex but this effect cancelled when controlling for ApoE4 genotype. Conclusions: Our findings showed that, among two SCD groups without objective deficits and same degree of subjective cognitive decline, only those who seek help for memory concern showed significant atrophy, with a topography consistent with early AD. In line with studies showing that worries associated with SCD increase the risk for AD, these findings highlight the relevance of memory clinic setting in selecting SCD with a high likelihood of developing AD. The degree of subjective cognitive decline in the general population may also be relevant but is probably associated to a more heterogeneous outcome. F5-01-04
SUBJECTIVE COGNITIVE CONCERNS AS AN EARLY INDICATOR OF ALZHEIMER’S DISEASE PATHOLOGY
Rebecca Amariglio, Massachusetts General Hospital, Boston, Massachusetts, United States. Contact e-mail: RAMARIGLIO@partners. org Background: Although self-reported cognitive concerns (SCC) have previously been dismissed as a sign of the “worried well”, there is emerging evidence to suggest that SCC may herald initial cognitive decrements at the stage of preclinical Alzheimer’s disease (AD). Recent preliminary data from our own group and others suggests that specific SCC may in fact indicate early awareness prior to objective impairment on standardized tests and may be associated with evidence of early pathology on AD biomarkers. Methods: Multimodality studies relating SCC with AD biomarker evidence