Study protocol for the Heads-Up trial: a phase II randomized controlled trial investigating head-up tilt sleeping to alleviate orthostatic intolerance in Parkinson's Disease and parkinsonism.

BACKGROUND: In persons with Parkinson's Disease (PD) or certain forms of atypical parkinsonism, orthostatic hypotension is common and disabling, yet often underrecognized and undertreated. About half of affected individuals also exhibit supine hypertension. This common co-occurrence of both orthostatic hypotension and supine hypertension complicates pharmacological treatments as the treatment of the one can aggravate the other. Whole-body head-up tilt sleeping (HUTS) is the only known intervention that may improve both. Evidence on its effectiveness and tolerability is, however, lacking, and little is known about the implementability. METHODS: In this double-blind multicenter randomized controlled trial (phase II) we will test the efficacy and tolerability of HUTS at different angles in 50 people with PD or parkinsonism who have both symptomatic orthostatic hypotension and supine hypertension. All participants start with one week of horizontal sleeping and subsequently sleep at three different angles, each maintained for two weeks. The exact intervention will vary between the randomly allocated groups. Specifically, the intervention group will consecutively sleep at 6°, 12° and 18°, while the delayed treatment group starts with a placebo angle (1°), followed by 6° and 12°. We will evaluate tolerability using questionnaires and compliance to the study protocol. The primary endpoint is the change in average overnight blood pressure measured by a 24-hour ambulatory blood pressure recording. Secondary outcomes include orthostatic blood pressure, orthostatic tolerance, supine blood pressure, nocturia and various other motor and non-motor tests and questionnaires. DISCUSSION: We hypothesize that HUTS can simultaneously alleviate orthostatic hypotension and supine hypertension, and that higher angles of HUTS are more effective but less tolerable. The Heads-Up trial will help to clarify the effectiveness, tolerability, and feasibility of this intervention at home and can guide at-home implementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT05551377; Date of registration: September 22, 2022.

Variability of cardioinhibition in vasovagal syncope: differences between subgroups during cardioinhibition and beyond.

PURPOSE: We compared hemodynamic parameters between subjects with marked, intermediate and minimal cardioinhibition during vasovagal syncope. METHODS: The study included subjects with a decrease in heart rate while experiencing a complete vasovagal syncope during tilt-table testing. The subjects were classified as having marked, intermediate or minimal cardioinhibition, based on tertile values of the decrease in heart rate. Hemodynamic parameters between these groups were compared before tilt in the supine position, shortly after tilt and during cardioinhibition. RESULTS: A total of 149 subjects with a median age of 43 (interquartile range 24-60) years were included in the study. Among the three groups with different levels of cardioinhibition, the highest heart rate was observed in subjects with marked cardioinhibition both before and shortly after tilt and at the start of cardioinhibition. The heart rate decrease in these subjects was both larger and faster compared to subjects with minimal and intermediate cardioinhibition. CONCLUSION: Subjects with marked cardioinhibition have both a larger and faster decrease in heart rate compared to subjects with intermediate and minimal cardioinhibition, as early as from the start of cardioinhibition. Marked cardioinhibition is related to differences in hemodynamic profiles already present well before the start of cardioinhibition.

Syncope Diagnosis at Referral to a Tertiary Syncope Unit: An in-Depth Analysis of the FAST II.

OBJECTIVE: A substantial number of patients with a transient loss of consciousness (T-LOC) are referred to a tertiary syncope unit without a diagnosis. This study investigates the final diagnoses reached in patients who, on referral, were undiagnosed or inaccurately diagnosed in secondary care. METHODS: This study is an in-depth analysis of the recently published Fainting Assessment Study II, a prospective cohort study in a tertiary syncope unit. The diagnosis at the tertiary syncope unit was established after history taking (phase 1), following autonomic function tests (phase 2), and confirming after critical follow-up of 1.5-2 years, with the adjudicated diagnosis (phase 3) by a multidisciplinary committee. Diagnoses suggested by the referring physician were considered the phase 0 diagnosis. We determined the accuracy of the phase 0 diagnosis by comparing this with the phase 3 diagnosis. RESULTS: 51% (134/264) of patients had no diagnosis upon referral (phase 0), the remaining 49% (130/264) carried a diagnosis, but 80% (104/130) considered their condition unexplained. Of the patients undiagnosed at referral, three major causes of T-LOC were revealed: reflex syncope (69%), initial orthostatic hypotension (20%) and psychogenic pseudosyncope (13%) (sum > 100% due to cases with multiple causes). Referral diagnoses were either inaccurate or incomplete in 65% of the patients and were mainly altered at tertiary care assessment to reflex syncope, initial orthostatic hypotension or psychogenic pseudosyncope. A diagnosis of cardiac syncope at referral proved wrong in 17/18 patients. CONCLUSIONS: Syncope patients diagnosed or undiagnosed in primary and secondary care and referred to a syncope unit mostly suffer from reflex syncope, initial orthostatic hypotension or psychogenic pseudosyncope. These causes of T-LOC do not necessarily require ancillary tests, but can be diagnosed by careful history-taking. Besides access to a network of specialized syncope units, simple interventions, such as guideline-based structured evaluation, proper risk-stratification and critical follow-up may reduce diagnostic delay and improve diagnostic accuracy for syncope.

Influence of Age on Magnitude and Timing of Vasodepression and Cardioinhibition in Tilt-Induced Vasovagal Syncope.

BACKGROUND: Cardioinhibition may diminish with age, but the changing balance of cardioinhibition and vasodepression with age has not been quantified, leaving the mechanism of vasovagal syncope (VVS) in old age unclear. OBJECTIVES: This study sought to quantify age-related changes of vasodepression and cardioinhibition in tilt-induced VVS. METHODS: We studied 163 cases of tilt-induced VVS, evoked using the Italian protocol with blood pressure, heart rate, and video-electroencephalographic monitoring. Presyncope was excluded. Cardioinhibition was defined as the heart rate decrease before syncope; asystolic pauses (≥3 seconds) were divided into early and late asystole, ie, beginning early enough to or too late to be the major cause of loss of consciousness. The log-ratio method was used to quantify contributions of cardioinhibition and vasodepression, assessed in 2 10-second periods before the onset of cardioinhibition and before syncope. RESULTS: With increasing age, cardioinhibition decreased, ie, heart rate decreased less and more slowly near syncope (P < 0.0001), while vasodepression increased. Asystolic pauses were less frequent in the older one-half of the group than the younger one-half (26% vs 57%; P < 0.00001), but when it did, late asystole occurred more often (58% vs 15%; P < 0.001). CONCLUSIONS: The shift toward less cardioinhibition and more vasodepression with increased age probably reflects a physiological shift in circulatory control. The weakening of cardioinhibition with age may detract from the efficacy of pacing in older patients with VVS. Cardioinhibition-vasodepression balance should be considered in pacing decisions in older subjects with VVS.

The pathophysiology of vasovagal syncope: Novel insights.

The pathophysiology of vasovagal syncope (VVS) is reviewed, focusing on hemodynamic aspects. Much more is known about orthostatic than about emotional VVS, probably because the former can be studied using a tilt table test (TTT). Recent advances made it possible to quantify the relative contributions of the three factors that control blood pressure: heart rate (HR), stroke volume (SV) and total peripheral resistance (TPR). Orthostatic VVS starts with venous pooling, reflected in a decrease of SV. This is followed by cardioinhibition (CI), which is a decrease of HR that accelerates the ongoing decrease of BP, making the start of CI a literal as well as fundamental turning point. The role of hormonal and other humoral factors, respiration and of psychological influences is reviewed in short, leading to the conclusion that a multidisciplinary approach to the study of the pathophysiology of VVS may yield new insights.

Novel Methods for Quantification of Vasodepression and Cardioinhibition During Tilt-Induced Vasovagal Syncope.

RATIONALE: Assessing the relative contributions of cardioinhibition and vasodepression to the blood pressure (BP) decrease in tilt-induced vasovagal syncope requires methods that reflect BP physiology accurately. OBJECTIVE: To assess the relative contributions of cardioinhibition and vasodepression to tilt-induced vasovagal syncope using novel methods. METHODS AND RESULTS: We studied the parameters determining BP, that is, stroke volume (SV), heart rate (HR), and total peripheral resistance (TPR), in 163 patients with tilt-induced vasovagal syncope documented by continuous ECG and video EEG monitoring. We defined the beginning of cardioinhibition as the start of an HR decrease (HR) before syncope and used logarithms of SV, HR, and TPR ratios to quantify the multiplicative relation BP=SV·HR·TPR. We defined 3 stages before syncope and 2 after it based on direction changes of these parameters. The earliest BP decrease occurred 9 minutes before syncope. Cardioinhibition was observed in 91% of patients at a median time of 58 seconds before syncope. At that time, SV had a strong negative effect on BP, TPR a lesser negative effect, while HR had increased (all P<0.001). At the onset of cardioinhibition, the median HR was at 98 bpm higher than baseline. Cardioinhibition thus initially only represented a reduction of the corrective HR increase but was nonetheless accompanied by an immediate acceleration of the ongoing BP decrease. At syncope, SV and HR contributed similarly to the BP decrease (P<0.001), while TPR did not affect BP. CONCLUSIONS: The novel methods allowed the relative effects of SV, HR, and TPR on BP to be assessed separately, although all act together. The 2 major factors lowering BP in tilt-induced vasovagal syncope were reduced SV and cardioinhibition. We suggest that the term vasodepression in reflex syncope should not be limited to reduced arterial vasoconstriction, reflected in TPR, but should also encompass venous pooling, reflected in SV.

Timing of Circulatory and Neurological Events in Syncope.

Syncope usually lasts less than a minute, in which short time arterial blood pressure temporarily falls enough to decrease brain perfusion so much that loss of consciousness ensues. Blood pressure decreases quickest when the heart suddenly stops pumping, which happens in arrhythmia and in severe cardioinhibitory reflex syncope. Loss of consciousness starts about 8 s after the last heart beat and circulatory standstill occurs after 10-15 s. A much slower blood pressure decrease can occur in syncope due to orthostatic hypotension Standing blood pressure can then stabilize at low values often causing more subtle signs (i.e., inability to act) but often not low enough to cause loss of consciousness. Cerebral autoregulation attempts to keep cerebral blood flow constant when blood pressure decreases. In reflex syncope both the quick blood pressure decrease and its low absolute value mean that cerebral autoregulation cannot prevent syncope. It has more protective value in orthostatic hypotension. Neurological signs are related to the severity and timing of cerebral hypoperfusion. Several unanswered pathophysiological questions with possible clinical implications are identified.

Use of mild cognitive impairment and prodromal AD/MCI due to AD in clinical care: a European survey.

INTRODUCTION: The diagnosis of mild cognitive impairment (MCI) refers to cognitive impairment not meeting dementia criteria. A survey among members of the American Association of Neurology (AAN) showed that MCI was considered a useful diagnosis. Recently, research criteria have been proposed for the diagnosis of Alzheimer's disease (AD) in MCI based on AD biomarkers (prodromal AD/MCI due to AD). The aim of this study was to investigate the attitudes of clinicians in Europe on the clinical utility of MCI and prodromal AD/MCI due to AD criteria. We also investigated whether the prodromal AD/MCI due to AD criteria impacted management of MCI patients. METHODS: An online survey was performed in 2015 among 102 members of the European Academy of Neurology (EAN) and the European Alzheimer's Disease Consortium (EADC). Questions were asked on how often criteria were used, how they were operationalized, how they changed patient management, and what were considered advantages and limitations of MCI and prodromal AD/MCI due to AD. The questionnaire consisted of 47 questions scored on a Likert scale. RESULTS: Almost all respondents (92%) used the MCI diagnosis in clinical practice. Over 80% of the EAN/EADC respondents found a MCI diagnosis useful because it helped to label the cognitive problem, involve patients in planning for the future, and start risk reduction activities. These findings were similar to those reported in the AAN survey. Research criteria for prodromal AD/MCI due to AD were used by 68% of the EAN/EADC respondents. The most common reasons to use the criteria were increased certainty of diagnosis (86%), increased possibilities to provide counseling (51%), facilitation of follow-up planning (48%), start of medical intervention (49%), and response to patients' wish for a diagnosis (41%). Over 70% of the physicians considered that a diagnosis of prodromal AD/MCI due to AD had an added value over the MCI diagnosis. CONCLUSIONS: The diagnostic criteria of MCI and prodromal AD/MCI due to AD are commonly used among EAN/EADC members. The prodromal AD/MCI due to AD were considered clinically useful and impacted patient management and communication.

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.

Measurements of medial temporal lobe atrophy for prediction of Alzheimer's disease in subjects with mild cognitive impairment.

Our aim was to compare the predictive accuracy of 4 different medial temporal lobe measurements for Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI). Manual hippocampal measurement, automated atlas-based hippocampal measurement, a visual rating scale (MTA-score), and lateral ventricle measurement were compared. Predictive accuracy for AD 2 years after baseline was assessed by receiver operating characteristics analyses with area under the curve as outcome. Annual cognitive decline was assessed by slope analyses up to 5 years after baseline. Correlations with biomarkers in cerebrospinal fluid (CSF) were investigated. Subjects with MCI were selected from the Development of Screening Guidelines and Clinical Criteria for Predementia AD (DESCRIPA) multicenter study (n = 156) and the single-center VU medical center (n = 172). At follow-up, area under the curve was highest for automated atlas-based hippocampal measurement (0.71) and manual hippocampal measurement (0.71), and lower for MTA-score (0.65) and lateral ventricle (0.60). Slope analysis yielded similar results. Hippocampal measurements correlated with CSF total tau and phosphorylated tau, not with beta-amyloid 1-42. MTA-score and lateral ventricle volume correlated with CSF beta-amyloid 1-42. We can conclude that volumetric hippocampal measurements are the best predictors of AD conversion in subjects with MCI.

Prediction of Alzheimer disease in subjects with amnestic and nonamnestic MCI.

OBJECTIVE: To compare the predictive accuracy of ß-amyloid (Aß)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 Aß1-42 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 Aß1-42, tau, Aß1-42/tau ratio, HCV, and APOE ε4 predicted AD-type dementia in each MCI subgroup with the same overall diagnostic accuracy. However, CSF Aß1-42 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 Alzheimer's Association criteria.

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 Alzheimer's 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 Alzheimer's Association (NIA-AA) in 2011. They both provide guidelines for the diagnosis of asymptomatic and symptomatic Alzheimer's 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.

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 Alzheimer's Disease (DESCRIPA) study. We included subjects with MCI, an abnormal level of ß-amyloid(1-42) (Aß(1-42)) 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 Aß(1-42) 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.

Injury markers but not amyloid markers are associated with rapid progression from mild cognitive impairment to dementia in Alzheimer's disease.

Alzheimer's 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 Aß1-42 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 Aß1-42, 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.

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 Alzheimer's 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 (Aß)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 Aß1-42/tau and HCV predicted AD-type dementia regardless of apolipoprotein E (APOE) genotype and cognitive scores. Test sequence analyses showed that CSF Aß1-42/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 Aß1-42/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.

[Unexceptional symptoms as expression of MELAS]. / Alledaagse symptomen als uiting van MELAS.

An 11-year-old girl and a 25-year-old woman were both initially referred to a neurologist with 'common' neurological problems: The girl suffered from tics, and later epilepsy, and her serum lactate concentration was elevated. She had unilateral hyperintensity of the left cerebral cortex and later developed diabetes mellitus. The woman had muscle weakness, diabetes mellitus and ptosis. In both patients, the problems turned out to be an expression of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). The first patient died at 18 years of age during an epileptic seizure with severe metabolic disturbances. The second patient developed bilateral perceptive hearing loss, epilepsy and cardiomyopathy and she was repeatedly admitted to hospital with stroke-like episodes. She died at 46 years of age. Both patients had the MELAS A3243G point mutation. MELAS is a maternally inherited mitochondrial disorder. The age of onset and symptoms are highly variable, even within one family. To date there are no curative treatment options for the disease. Diagnosing MELAS is important though, for optimising the treatment of the individual symptoms and genetic counselling.

Biomarkers as predictors for conversion from mild cognitive impairment to Alzheimer-type dementia: implications for trial design.

Disease modifying drugs for Alzheimer's disease (AD) are likely to be most effective when given in non-demented subjects. In this review we summarized biomarkers in cerebrospinal fluid (CSF) and blood that can predict AD-type dementia in subjects with mild cognitive impairment (MCI). In addition, we investigated whether these markers could reduce sample size and costs if used to select subjects for trials on the prevention of AD in subjects with MCI. A meta-analysis of markers that had been investigated in multiple studies showed that the combination of amyloid-beta (Abeta1-42 and tau in CSF had the best predictive accuracy for AD (odds ratio (OR) 18.1, 95% confidence interval (CI) 9.6-32.4). Abeta1-42, total tau, and phosphorylated tau in CSF also predicted conversion, but with lower accuracy (OR 7.5 to 8.1). Plasma levels of Abeta1-40, Abeta1-42, the ratio Abeta1-42/Abeta1-40 and homocysteine did not predict outcome. In a fictive trial design, the use of the combination of Abeta1-42 and tau in CSF in the selection of subjects could reduce sample size by 67% and trial costs by 60% compared to a trial in which unselected subjects with MCI would be enrolled. In conclusion, the combination of Abeta1-42 and tau in CSF is useful to select subjects for trials that aim to slow down the progression from MCI to AD-type dementia.