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.

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.

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.

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 (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.

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.

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 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.

Rationale: Assessing the relative contributions of cardioinhibition and vasodepression to the blood pressure (BP) decrease in tilt-induced vasovagal syncope (T-VVS) requires methods that reflect BP physiology accurately. Objective: To assess the relative contributions of cardioinhibition and vasodepression to T-VVS using novel methods. Methods and Results: We studied the parameters determining BP, i.e. stroke volume (SV), heart rate (HR) and total peripheral resistance (TPR), in 163 patients with T-VVS documented by continuous ECG and video EEG monitoring. We defined the beginning of cardioinhibition as the start of a heart rate decrease (HR) before syncope, and used logarithms of SV-, HR- and TPR-ratios to quantify the multiplicative relation BP=SV·HR·TPR. We defined three stages before syncope and two after it based on direction changes of these parameters. The earliest BP decrease occurred nine minutes before syncope. Cardioinhibition was observed in 91% of patients at a median time of 58 s. 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, 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, even though all act together. The two major factors lowering BP in T-VVS 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.

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.