Ineke van Rossum

Injury markers predict time to dementia in subjects with MCI and amyloid pathology

Objectives: Alzheimer disease (AD) can now be diagnosed in subjects with mild cognitive impairment (MCI) using biomarkers. However, little is known about the rate of decline in those subjects. In this cohort study, we aimed to assess the conversion rate to dementia and identify prognostic markers in subjects with MCI and evidence of amyloid pathology. Methods: We pooled subjects from the VU University Medical Center Alzheimer Center and the Development of Screening Guidelines and Criteria for Predementia Alzheimers Disease (DESCRIPA) study. We included subjects with MCI, an abnormal level of β-amyloid1−42 (Aβ1–42) in the CSF, and at least one diagnostic follow-up visit. We assessed the effect of APOE genotype, CSF total tau (t-tau) and tau phosphorylated at threonine 181 (p-tau) and hippocampal volume on time to AD-type dementia using Cox proportional hazards models and on decline on the Mini-Mental State Examination (MMSE) using linear mixed models. Results: We included 110 subjects with MCI with abnormal CSF Aβ1–42 and a mean MMSE score of 26.3 ± 2.8. During a mean follow-up of 2.2 ± 1.0 (range 0.4–5.0) years, 63 subjects (57%) progressed to AD-type dementia. Abnormal CSF t-tau (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.1–4.6, p = 0.03) and CSF p-tau (HR 3.5, 95% CI 1.3–9.2, p = 0.01) concentration and hippocampal atrophy (HR 2.5, 95% CI 1.1–5.6, p = 0.02) predicted time to dementia. For subjects with both abnormal t-tau concentration and hippocampal atrophy, HR was 7.3 (95% CI 1.0–55.9, p = 0.06). Furthermore, abnormal CSF t-tau and p-tau concentrations and hippocampal atrophy predicted decline in MMSE score. Conclusions: In subjects with MCI and evidence of amyloid pathology, the injury markers CSF t-tau and p-tau and hippocampal atrophy can predict further cognitive decline.

Prediction of Alzheimer disease in subjects with amnestic and nonamnestic MCI

Objective: To compare the predictive accuracy of β-amyloid (Aβ)1–42 and total tau in CSF, hippocampal volume (HCV), and APOE genotype for Alzheimer disease (AD)-type dementia in subjects with amnestic mild cognitive impairment (aMCI) and nonamnestic mild cognitive impairment (naMCI). Methods: We selected 399 subjects with aMCI and 226 subjects with naMCI from a multicenter memory clinic–based cohort. We measured CSF Aβ1–42 and tau by ELISA (n = 231), HCV on MRI (n = 388), and APOE ε4 (n = 523). Follow-up was performed annually up to 5 years. Outcome measures were progression to AD-type dementia and cognitive decline. Results: At least 1 follow-up was available for 538 subjects (86%). One hundred thirty-two subjects with aMCI (38%) and 39 subjects with naMCI (20%) progressed to AD-type dementia after an average follow-up of 2.5 years. CSF Aβ1–42, tau, Aβ1–42/tau ratio, HCV, and APOE ε4 predicted AD-type dementia in each MCI subgroup with the same overall diagnostic accuracy. However, CSF Aβ1–42 concentration was higher and hippocampal atrophy less severe in subjects with naMCI compared with aMCI. This reduced the sensitivity but increased the specificity of these markers for AD-type dementia in subjects with naMCI. Conclusions: AD biomarkers are useful to predict AD-type dementia in subjects with aMCI and naMCI. However, biomarkers might not be as sensitive for early diagnosis of AD in naMCI compared with aMCI. This may have implications for clinical implementation of the National Institute on Aging and Alzheimers Association criteria.

Test sequence of CSF and MRI biomarkers for prediction of AD in subjects with MCI

Our aim was to identify the best diagnostic test sequence for predicting Alzheimers disease (AD)-type dementia in subjects with mild cognitive impairment (MCI) using cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers. We selected 153 subjects with mild cognitive impairment from a multicenter memory clinic-based cohort. We tested the CSF beta amyloid (Aβ)1-42/tau ratio using enzyme-linked immunosorbent assay (ELISA) and hippocampal volumes (HCVs) using the atlas-based learning embeddings for atlas propagation (LEAP) method. Outcome measure was progression to AD-type dementia in 2 years. At follow-up, 48 (31%) subjects converted to AD-type dementia. In multivariable analyses, CSF Aβ1-42/tau and HCV predicted AD-type dementia regardless of apolipoprotein E (APOE) genotype and cognitive scores. Test sequence analyses showed that CSF Aβ1-42/tau increased predictive accuracy in subjects with normal HCV (p < 0.001) and abnormal HCV (p = 0.025). HCV increased predictive accuracy only in subjects with normal CSF Aβ1-42/tau (p = 0.014). Slope analyses for annual cognitive decline yielded similar results. For selection of subjects for a prodromal AD trial, the best balance between sample size and number of subjects needed to screen was obtained with CSF markers. These results provide further support for the use of CSF and magnetic resonance imaging biomarkers to identify prodromal AD.

Injury Markers but not Amyloid Markers are Associated with Rapid Progression from Mild Cognitive Impairment to Dementia in Alzheimer's Disease

Alzheimers disease (AD) is a common cause of mild cognitive impairment (MCI). However, the time between the diagnosis of MCI and the diagnosis of dementia is highly variable. In this study we investigated which known risk factors and biomarkers of AD pathology were associated with rapid progression from MCI to dementia. Of the 203 subjects with MCI, 91 progressed to AD-type dementia and were considered to have MCI-AD at baseline. Subjects with MCI-AD were older, more frequently female and carrier of the APOE-ε4 allele, had lower scores on the Mini-Mental State Examination (MMSE), more medial temporal lobe atrophy (MTA) and lower levels of Aβ1-42 and increased levels of t-tau and p-tau in the cerebrospinal fluid (CSF) compared to subjects without AD-type dementia at follow up. Of the 91 subjects with MCI-AD, we had data available of CSF (n = 56), MTA (n = 76), and APOE-genotype (n = 63). Among the subjects with MCI-AD, MTA (hazard ratio (HR) 2.2, p = 0.004) and low MMSE score (HR 2.0 p = 0.007) were associated with rapid progression to dementia. High CSF t-tau (HR 1.7, p = 0.07) and p-tau (1.7, p = 0.08) tended to be associated with rapid progression to dementia. CSF Aβ1-42, APOE status, age, gender, and educational level were not associated with time to dementia. Our findings implicate a different role for biomarkers in diagnosis and prognosis of MCI-AD. While amyloid markers can be used to identify MCI-AD, injury markers may predict rapid progression to dementia.

Comparison of International Working Group criteria and National Institute on Aging–Alzheimer’s Association criteria for Alzheimer’s disease

Two sets of research criteria for Alzheimers disease are now available: those published by an International Working Group in 2007, and the recommendations published by the National Institute on Aging and the Alzheimers Association (NIA–AA) in 2011. They both provide guidelines for the diagnosis of asymptomatic and symptomatic Alzheimers disease. The coexistence of two sets of criteria for the same disorder raises the question of which set of criteria should be preferred. A comparison of the criteria revealed differences in approach, terminology, and use of cognitive markers and biomarkers. Most persons who meet the International Working Group criteria will also meet the NIA–AA criteria and vice versa. However, the NIA–AA criteria allow for a subclassification of persons based on biomarker results within each diagnostic category. Further research is needed to validate the criteria. Modifications are likely to be made before the criteria can be used in daily practice.

24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial

Summary Background Nutrition is an important modifiable risk factor in Alzheimers disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimers disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimers disease. Here, we report the 24-month results of the trial. Methods LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimers disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705. Findings Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was −0·028 (SD 0·453) in the active group and −0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI −0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of −0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention. Interpretation The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimers disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed. Funding European Commission 7th Framework Programme.

Cerebrospinal fluid markers for predicting Alzheimer's-type dementia in subjects with amnestic versus non-amnestic mild cognitive impairment

Background: Familial Alzheimer’s disease (FAD) is most commonly caused bymutations in the Presenilin 1 (PSEN1) and amyloid precursor protein (APP) genes. We explored the associated clinical phenotype through analysis of the cohort of symptomatic individuals from FAD families studied at our centre over the past two decades. Methods: Clinical history and neurological examination findings were recorded for 100 individuals with FAD secondary to mutations in PSEN1 (n 1⁄4 70) or APP (n 1⁄4 30). These were reviewed to ascertain the earliest cognitive symptoms and presence of additional neurological features during the disease. Results: The majority of the cohort had previously reported mutations. One subject had a novel APP (T719N) mutation and four had novel PSEN1 mutations (S132A, Q222P, F283L and the T291A and A434T substitutions, which were both found in the same individual). Mean (standard deviation) age at onset was 43.2 (7.3) for the PSEN1 and 50.7 (5.2) for the APP group. Memory impairment was the earliest cognitive symptom in 97% of APP and 83% of PSEN1 patients. The presenting symptom in the remainder of the APP group was dyscalculia. In the PSEN1 group it was behavioural change in 11%, language impairment in 3% and dyscalculia in 3%. 30% of APP patients had myoclonus and 27% had seizures. In the PSEN1 cohort, 50% had myoclonus, 21% had seizures, 20% had pyramidal signs, usually spastic paraparesis, 16% had extrapyramidal signs and 3% had cerebellar signs. Conclusions: Amnestic presentations occurred in the majority of individuals with FAD, particularly those with APP mutations. Initial symptoms could, however, relate to behaviour, language or calculation skills. Myoclonus and seizures occurred relatively frequently with both mutations. Spastic paraparesis and extrapyramidal signs were not uncommon in the PSEN1 group. FAD should be considered in young patients with dementia and additional neurological features, particularly if the family history is censored. Recognition of families affected by FAD is becoming increasingly important now that opportunities for individuals at risk of the disease to join presymptomatic treatment trials are on the horizon. O2-13-03 CEREBROSPINAL FLUID MARKERS FOR PREDICTINGALZHEIMER’S-TYPEDEMENTIA IN SUBJECTS WITH AMNESTIC VERSUS NONAMNESTIC MILD COGNITIVE IMPAIRMENT Stephanie Vos, Ineke van Rossum, Frans Verhey, Hilkka Soininen, Lars-Olof Wahlund, Harald Hampel, Magda Tsolaki, Lennart Minthon, Wiesje Van der Flier, Charlotte Teunissen, Kaj Blennow, Philip Scheltens, Pieter Jelle Visser, Maastricht University, Maastricht, Netherlands; Alzheimer Center, VU Medical Center, Amsterdam, Netherlands; 3 University and University Hospital of Kuopio, Kuopio, Finland; 4 Karolinska Institutet, Huddinge, Sweden; 5 Goethe-University, Frankfurt/Main, Germany; Aristotle University of Thessaloniki, Memory and Dementia Center, Thessaloniki, Greece; Lund University, Malm€o, Sweden; 8 VU University Medical Center, Amsterdam, Netherlands; 9 G€oteborg University, M€olndal, Sweden.

High CSF tau predicts rapid decline to Alzheimer's type dementia in MCI subjects with abnormal CSF Aß1-42

patients (conversion to AD during follow-up). Data will be analyzed by means of survival analysis. We here present preliminary results of 100 patients as follow-up, data collection and data analyses are still running. The final dataset will be presented at the ICAD meeting in July 2011. Results: Preliminary data analysis comprises 50 stable MCI patients and 50 progressive MCI patients. The mean follow-up period is respectively 18,7 (12,0) months and 25,6 (17,8) months. The two groups differed significantly in MFS total scores and the MFS item score ‘loss of insight and judgment’. Mean MFS total score was 1,98 for stable MCI and 2,70 for progressive MCI patients. Multivariate analysis showed an increased risk of 59% for developing AD by each raise of one point on the MFS total score. Also, age increase of 1 year was linked to an increased risk of 42% for developing AD. Conclusions: The presence of frontal lobe symptoms inMCI showed to have an impact on the risk of conversion to AD. Consequently, these symptoms may have a prognostic value. Likewise, other behavioral symptoms should be investigated on their potential prognostic value.

Strong Relation Between an EEG Functional Connectivity Measure and Postmenstrual Age: A New Potential Tool for Measuring Neonatal Brain Maturation

Fetal and neonatal brain connectivity development is highly complex. Studies have shown that functional networks change dramatically during development. The purpose of the current study was to determine how the mean phase lag index (mPLI), a measure of functional connectivity (FC), assessed with electroencephalography (EEG), changes with postmenstrual age (PMA) during the early stages of brain development after birth. Neonates (N = 131) with PMA 27.6–45.3 weeks who underwent an EEG for a medical reason were retrospectively studied. For each recording, global FC was assessed by obtaining a whole-head average of all local PLI values (pairwise between sensor space EEG signals). Global FC results were consequently correlated with PMA values in seven frequency bands. Local results were obtained for the frequency band with the strongest global association. There was a strong negative correlation between mPLI and PMA in most frequency bands. The strongest association was found in the delta frequency band (R = −0.616, p < 0.001) which was therefore topographically explored; the strongest correlations were between pairs of electrodes with at least one electrode covering the central sulcus. Even in this heterogeneous group of neonates, global FC strongly reflects PMA. The decrease in PLI may reflect the process of segregation of specific brain regions with increasing PMA. This was mainly found in the central brain regions, in parallel with myelination of these areas during early development. In the future, there may be a role for PLI in detecting atypical FC maturation. Moreover, PLI could be used to develop biomarkers for brain maturation and expose segregation processes in the neonatal brain.

MRI traits identify several loci influencing degeneration of the hippocampus lobe atrophy in the prediction of Alzheimer's disease in subjects with MCI

Age at exam (years) 75.0 (72.5-78.5) 75.9 (70.0-80.5) 73.7 (68.5-80.0) 0.78 Education (years) 14.0 (13.0-16.5) 16.0 (14.0-18.0) 15.5 (12.0-17.0) 0.06 Gender (% male) 47.8% 59% 56% 0.57 APOE4 (% APOE4 positive) 13% 55.2% 76% <0.0001 MMSE 29.0 (29.0-30.0) 27.0 (25.0-28.0) 24.0 (22.0-25.0) <0.0001 Modified ADASCog 4.8 (3.7-6.7) 11.7 (9.0-14.7) 17.7 (14.0-21.3) <0.0001 SPARE-AD -1.41 (-1.81 to -0.32) 1.2 (0.6-1.6) 1.2 (0.3-1.7) <0.0001 CSF measurements available (%) 95.7% 52.1% 92.0% Ab42 (ng/mL) 251.5 (233.0-268.0) 144.5 (125.5-189.0) 134.0 (122.0-160.0) <0.0001 T-tau (ng/mL) 56.0 (53.0-62.0) 88.5 (65.0-117.0) 112.5 (69.0-150) <0.0001 P-Tau (ng/mL) 19.5 (16.0-22.0) 33.0 (22.0-45.0) 36.5 (26.0-47.0) <0.0001 Subjects with pathological CSF 0/20 81/112 41/46 <0.0001