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1.  Eyes-closed task-free electroencephalography in clinical trials for Alzheimer’s disease: an emerging method based upon brain dynamics 
Electroencephalography (EEG) is a longstanding technique to measure electrical brain activity and thereby an indirect measure of synaptic activity. Synaptic dysfunction accompanies Alzheimer’s disease (AD) and EEG can be regarded as a potentially useful biomarker in this disease. Lately, emerging analysis techniques of time series have become available for EEG, such as functional connectivity and network analysis, which have increased the possibilities for use in AD clinical trials. In this review, we report the EEG changes in the course of AD, including slowing of the EEG oscillations, decreased functional connectivity in the higher-frequency bands, and decline in optimal functional network organization. We discuss the use of EEG in clinical trials and provide directions for future research.
PMCID: PMC4304266  PMID: 25621017
2.  Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies 
Human molecular genetics  2014;23(23):6139-6146.
Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson’s and Alzheimer’s diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
PMCID: PMC4222357  PMID: 24973356
3.  Treating Alzheimer’s disease with monoclonal antibodies: current status and outlook for the future 
In the past decade, Alzheimer’s disease drug discovery has been directed at ‘disease modifying drugs’ that are able to counteract the progression of Alzheimer’s disease by intervening in specific parts of its neuropathological process. Passive immunization with monoclonal antibodies (mAbs) may be able to clear toxic amyloid-β species either directly or through microglia or complement activation, thereby halting the amyloid cascade and preventing neurodegeneration and cognitive and functional decline. Thus far, results from two large phase 3 trial programs with bapineuzumab and solaneuzumab, respectively, have brought rather disappointing results. Possible explanations could be that these compounds were either targeting the wrong amyloid-β species, or were given too late in the disease process. Several new mAbs targeting various amyloid-β epitopes are now being tested in ongoing phase 2 and 3 clinical trials. The present review discusses the various mAbs aimed at amyloid-β, summarizes trial results and provides an outlook for the future.
PMCID: PMC3978826  PMID: 24216217
4.  Plasma homocysteine, Alzheimer and cerebrovascular pathology: a population-based autopsy study 
Brain  2013;136(9):2707-2716.
Elevated plasma total homocysteine is associated with increased risk of dementia/Alzheimer’s disease, but underlying pathophysiological mechanisms are not fully understood. This study investigated possible links between baseline homocysteine, and post-mortem neuropathological and magnetic resonance imaging findings up to 10 years later in the Vantaa 85+ population including people aged ≥85 years. Two hundred and sixty-five individuals had homocysteine and autopsy data, of which 103 had post-mortem brain magnetic resonance imaging scans. Methenamine silver staining was used for amyloid-β and modified Bielschowsky method for neurofibrillary tangles and neuritic plaques. Macroscopic infarcts were identified from cerebral hemispheres, brainstem and cerebellum slices. Standardized methods were used to determine microscopic infarcts, cerebral amyoloid angiopathy, and α-synuclein pathology. Magnetic resonance imaging was used for visual ratings of the degree of medial temporal lobe atrophy, and periventricular and deep white matter hyperintensities. Elevated baseline homocysteine was associated with increased neurofibrillary tangles count at the time of death: for the highest homocysteine quartile, odds ratio (95% confidence interval) was 2.60 (1.28–5.28). The association was observed particularly in people with dementia, in the presence of cerebral infarcts, and with longer time between the baseline homocysteine assessment and death. Also, elevated homocysteine tended to relate to amyloid-β accumulation, but this was seen only with longer baseline-death interval: odds ratio (95% confidence interval) was 2.52 (0.88–7.19) for the highest homocysteine quartile. On post-mortem magnetic resonance imaging, for the highest homocysteine quartile odds ratio (95% confidence interval) was 3.78 (1.12–12.79) for more severe medial temporal atrophy and 4.69 (1.14–19.33) for more severe periventricular white matter hyperintensities. All associations were independent of several potential confounders, including common vascular risk factors. No relationships between homocysteine and cerebral macro- or microinfarcts, cerebral amyoloid angiopathy or α-synuclein pathology were detected. These results suggest that elevated homocysteine in adults aged ≥85 years may contribute to increased Alzheimer-type pathology, particularly neurofibrillary tangles burden. This effect seems to be more pronounced in the presence of cerebrovascular pathology. Randomized controlled trials are needed to determine the impact of homocysteine-lowering treatments on dementia-related pathology.
PMCID: PMC3754457  PMID: 23983028
homocysteine; Alzheimer’s disease; Alzheimer pathology; cerebrovascular pathology; elderly
5.  Widespread Disruption of Functional Brain Organization in Early-Onset Alzheimer’s Disease 
PLoS ONE  2014;9(7):e102995.
Early-onset Alzheimer’s disease (AD) patients present a different clinical profile than late-onset AD patients. This can be partially explained by cortical atrophy, although brain organization might provide more insight. The aim of this study was to examine functional connectivity in early-onset and late-onset AD patients. Resting-state fMRI scans of 20 early-onset (<65 years old), 28 late-onset (≥65 years old) AD patients and 15 “young” (<65 years old) and 31 “old” (≥65 years old) age-matched controls were available. Resting-state network-masks were used to create subject-specific maps. Group differences were examined using a non-parametric permutation test, accounting for gray-matter. Performance on five cognitive domains were used in a correlation analysis with functional connectivity in AD patients. Functional connectivity was not different in any of the RSNs when comparing the two control groups (young vs. old controls), which implies that there is no general effect of aging on functional connectivity. Functional connectivity in early-onset AD was lower in all networks compared to age-matched controls, where late-onset AD showed lower functional connectivity in the default-mode network. Functional connectivity was lower in early-onset compared to late-onset AD in auditory-, sensory-motor, dorsal-visual systems and the default mode network. Across patients, an association of functional connectivity of the default mode network was found with visuoconstruction. Functional connectivity of the right dorsal visual system was associated with attention across patients. In late-onset AD patients alone, higher functional connectivity of the sensory-motor system was associated with poorer memory performance. Functional brain organization was more widely disrupted in early-onset AD when compared to late-onset AD. This could possibly explain different clinical profiles, although more research into the relationship of functional connectivity and cognitive performance is needed.
PMCID: PMC4117463  PMID: 25080229
6.  Identifying target groups for the prevention of depression among caregivers of dementia patients 
Depression in informal caregivers of persons with dementia is a major, costly and growing problem. However, it is not yet clear which caregivers are at increased risk of developing depression. With this knowledge preventive strategies could focus on these groups to maximize health gain and minimize effort.
The onset of clinically relevant depression was measured with the Center for Epidemiologic Studies - Depression Scale in 725 caregivers who were not depressed at baseline and who were providing care for a relative with dementia. Caregivers were followed over 18 months. The indices calculated to identify the most important risk indicators were: odds ratio, attributable fraction, exposure rate and number needing to be treated.
The following significant indicators of depression onset were identified: increased initial depressive symptoms, poor self-rated health status and white or Hispanic race/ethnicity. The incidence of depression would decrease by 72.3% (attributive fraction) if these risk indicators together are targeted by a completely effective intervention. Race/ethnicity was not a significant predictor if caregivers of patients who died or were institutionalized were left out of the analyses.
Detection of only a few characteristics makes it possible to identify high-risk groups in an efficient way. Focusing on these easy-to-assess characteristics might contribute to a cost-effective prevention of depression in caregivers.
PMCID: PMC4104488  PMID: 21880175
incidence; high-risk groups; risk factors; carers; Alzheimer’s disease
7.  The effect of galantamine on brain atrophy rate in subjects with mild cognitive impairment is modified by apolipoprotein E genotype: post-hoc analysis of data from a randomized controlled trial 
The aim of this investigation was to assess the effect of galantamine, an acetylcholinesterase inhibitor and allosteric modulator of nicotinic receptors, on brain atrophy in individuals with mild cognitive impairment (MCI), and to assess effect modification by apolipoprotein E (APOE) genotype.
We used data from the Galantamine-International-11 (Gal-Int-11) trial, a 24-month, randomized, double blind, placebo-controlled, flexible-dose (16 to 24 mg daily) study in patients with MCI. Brain magnetic resonance imaging (MRI), including a 3-dimensional T1-weighted gradient echo volumetric sequence, was performed at screening and at 24 months. We recorded whole brain and hippocampal volumes, and calculated annual atrophy rates. Linear regression analysis was used to calculate adjusted mean differences in the rate of whole brain and hippocampal atrophy, between MCI patients treated with galantamine and with placebo. Additionally, we performed stratified analyses according to APOE genotype.
Data from 364 MCI patients with 24-month MRI data (galantamine, n = 176; placebo, n = 188) were included in the volumetric analysis. Subjects treated with galantamine demonstrated a lower rate of whole brain atrophy compared to those treated with placebo (adjusted mean difference 0.18% per year (95% confidence interval (CI) 0.04; 0.30)). Stratified analyses according to APOE genotype, showed that this effect was confined to patients who carried an APOE ϵ4 allele (adjusted mean difference 0.28% per year (95% CI 0.07; 0.50)). Rates of hippocampal atrophy did not differ significantly between study groups.
Patients with MCI who were treated with galantamine demonstrated a lower rate of whole brain atrophy, but not of hippocampal atrophy, over a 24-month treatment period, compared to those treated with placebo. This protective effect of galantamine on whole brain atrophy rate in MCI was only present in APOE ϵ4 carriers.
PMCID: PMC4255389  PMID: 25478019
8.  Altered distribution of the EphA4 kinase in hippocampal brain tissue of patients with Alzheimer’s disease correlates with pathology 
Synaptic dysfunction occurs early in the progression of Alzheimer’s disease (AD) and correlates with memory decline. There is emerging evidence that deregulation of Erythropoietin-producing hepatocellular (Eph) receptor tyrosine kinases (RTK) signaling contributes to the aberrant synaptic functions associated with neurodegeneration. The Eph receptor A4 is highly expressed in human adult hippocampal brain tissue and was previously linked to cognitive impairment in a transgenic mouse model for AD. Whether EphA4 levels are altered in AD brain remains elusive. Therefore we investigated the protein levels and localization of EphA4 in human hippocampus derived from AD (n = 29) as well as non-demented control cases (n = 19).
The total EphA4 protein levels were not changed in AD patients compared to control cases. However, immunohistochemical localization of EphA4 revealed an altered distribution in AD compared to control hippocampus. EphA4 immunoreactivity was observed in plaque-like structures in AD cases. Double-labelling with phosphorylated tau and amyloid beta indicates that EphA4 co-localizes with neuritic plaques in AD. This altered distribution pattern was observed at early stages (Braak stage II) and correlates with the hallmarks of AD pathology suggesting a reduced availability of EphA4 that is likely to contribute to synaptic dysfunction that occurs early in AD.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-014-0079-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4149234  PMID: 25027113
Alzheimer’s disease; EphA4 kinase; Synapse; Immunohistochemistry
9.  Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies 
Human Molecular Genetics  2014;23(23):6139-6146.
Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
PMCID: PMC4222357  PMID: 24973356
10.  Variability of CSF Alzheimer’s Disease Biomarkers: Implications for Clinical Practice 
PLoS ONE  2014;9(6):e100784.
Cerebrospinal fluid (CSF) biomarkers are increasingly being used for diagnosis of Alzheimer’s disease (AD).
We investigated the influence of CSF intralaboratory and interlaboratory variability on diagnostic CSF-based AD classification of subjects and identified causes of this variation.
We measured CSF amyloid-β (Aβ) 1-42, total tau (t-tau), and phosphorylated tau (p-tau) by INNOTEST enzyme-linked-immunosorbent assays (ELISA) in a memory clinic population (n = 126). Samples were measured twice in a single or two laboratories that served as reference labs for CSF analyses in the Netherlands. Predefined cut-offs were used to classify CSF biomarkers as normal or abnormal/AD pattern.
CSF intralaboratory variability was higher for Aβ1-42 than for t-tau and p-tau. Reanalysis led to a change in biomarker classification (normal vs. abnormal) of 26% of the subjects based on Aβ1-42, 10% based on t-tau, and 29% based on p-tau. The changes in absolute biomarker concentrations were paralleled by a similar change in levels of internal control samples between different assay lots. CSF interlaboratory variability was higher for p-tau than for Aβ1-42 and t-tau, and reanalysis led to a change in biomarker classification of 12% of the subjects based on Aβ1-42, 1% based on t-tau, and 22% based on p-tau.
Intralaboratory and interlaboratory CSF variability frequently led to change in diagnostic CSF-based AD classification for Aβ1-42 and p-tau. Lot-to-lot variation was a major cause of intralaboratory variability. This will have implications for the use of these biomarkers in clinical practice.
PMCID: PMC4069102  PMID: 24959687
11.  The association of angiotensin-converting enzyme with biomarkers for Alzheimer’s disease 
Lower angiotensin-converting enzyme (ACE) activity could increase the risk of Alzheimer’s disease (AD) as ACE functions to degrade amyloid-β (Aβ). Therefore, we investigated whether ACE protein and activity levels in cerebrospinal fluid (CSF) and serum were associated with CSF Aβ, total tau (tau) and tau phosphorylated at threonine 181 (ptau).
We included 118 subjects from our memory clinic-based Amsterdam Dementia Cohort (mean age 66 ± 8 years) with subjective memory complaints (n = 40) or AD (n = 78), who did not use antihypertensive drugs. We measured ACE protein levels (ng/ml) and activity (RFU) in CSF and serum, and amyloid β1–42, tau and ptau (pg/ml) in CSF.
Cross-sectional regression analyses showed that ACE protein level and activity in CSF and serum were lower in patients with AD compared to controls. Lower CSF ACE protein level, and to a lesser extent serum ACE protein level and CSF ACE activity, were associated with lower CSF Aβ, indicating more brain Aβ pathology; adjusted regression coefficients (B) (95% CI) per SD increase were 0.09 (0.04; 0.15), 0.06 (0.00; 0.12) and 0.05 (0.00; 0.11), respectively. Further, lower CSF ACE protein level was associated with lower CSF tau and ptau levels; adjusted B’s (95% CI) per SD increase were 0.15 (0.06; 0.25) and 0.17 (0.10; 0.25), respectively.
These results strengthen the hypothesis that ACE degrades Aβ. This could suggest that lowering ACE levels by for example ACE-inhibitors might have adverse consequences for patients with, or at risk for AD.
PMCID: PMC4075229  PMID: 24987467
12.  Imaging markers for Alzheimer disease 
Neurology  2013;81(5):487-500.
Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, 18F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured (“metric”: visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR−), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR− between 0.25 and 0.08, whereas prognostic LR+ and LR− were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR− from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR−. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR−. Within markers, the largest proportion of diagnostic LR+ and LR− variability was within 18F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.
PMCID: PMC3776529  PMID: 23897875
13.  The Effect of Souvenaid on Functional Brain Network Organisation in Patients with Mild Alzheimer’s Disease: A Randomised Controlled Study 
PLoS ONE  2014;9(1):e86558.
Synaptic loss is a major hallmark of Alzheimer’s disease (AD). Disturbed organisation of large-scale functional brain networks in AD might reflect synaptic loss and disrupted neuronal communication. The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to enhance synapse formation and function and has been shown to improve memory performance in patients with mild AD in two randomised controlled trials.
To explore the effect of Souvenaid compared to control product on brain activity-based networks, as a derivative of underlying synaptic function, in patients with mild AD.
A 24-week randomised, controlled, double-blind, parallel-group, multi-country study.
179 drug-naïve mild AD patients who participated in the Souvenir II study.
Patients were randomised 1∶1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks.
In a secondary analysis of the Souvenir II study, electroencephalography (EEG) brain networks were constructed and graph theory was used to quantify complex brain structure. Local brain network connectivity (normalised clustering coefficient gamma) and global network integration (normalised characteristic path length lambda) were compared between study groups, and related to memory performance.
The network measures in the beta band were significantly different between groups: they decreased in the control group, but remained relatively unchanged in the active group. No consistent relationship was found between these network measures and memory performance.
The current results suggest that Souvenaid preserves the organisation of brain networks in patients with mild AD within 24 weeks, hypothetically counteracting the progressive network disruption over time in AD. The results strengthen the hypothesis that Souvenaid affects synaptic integrity and function. Secondly, we conclude that advanced EEG analysis, using the mathematical framework of graph theory, is useful and feasible for assessing the effects of interventions.
Trial registration
Dutch Trial Register NTR1975.
PMCID: PMC3903587  PMID: 24475144
15.  The S-Connect study: results from a randomized, controlled trial of Souvenaid in mild-to-moderate Alzheimer’s disease 
Souvenaid® containing Fortasyn® Connect is a medical food designed to support synapse synthesis in persons with Alzheimer’s disease (AD). Fortasyn Connect includes precursors (uridine monophosphate; choline; phospholipids; eicosapentaenoic acid; docosahexaenoic acid) and cofactors (vitamins E, C, B12, and B6; folic acid; selenium) for the formation of neuronal membranes. Whether Souvenaid slows cognitive decline in treated persons with mild-to-moderate AD has not been addressed.
In a 24-week, double-masked clinical trial at 48 clinical centers, 527 participants taking AD medications [52% women, mean age 76.7 years (Standard Deviation, SD = 8.2), and mean Mini-Mental State Examination score 19.5 (SD = 3.1, range 14–24)] were randomized 1:1 to daily, 125-mL (125 kcal), oral intake of the active product (Souvenaid) or an iso-caloric control. The primary outcome of cognition was assessed by the 11-item Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog). Compliance was calculated from daily diary recordings of product intake. Statistical analyses were performed using mixed models for repeated measures.
Cognitive performance as assessed by ADAS-cog showed decline over time in both control and active study groups, with no significant difference between study groups (difference =0.37 points, Standard Error, SE = 0.57, p = 0.513). No group differences in adverse event rates were found and no clinically relevant differences in blood safety parameters were noted. Overall compliance was high (94.1% [active] and 94.5% [control]), which was confirmed by significant changes in blood (nutritional) biomarkers.
Add-on intake of Souvenaid during 24 weeks did not slow cognitive decline in persons treated for mild-to-moderate AD. Souvenaid was well tolerated in combination with standard care AD medications.
Trial registration
Dutch Trial Register number: NTR1683.
PMCID: PMC3978853  PMID: 24280255
16.  The cost-effectiveness of a family meetings intervention to prevent depression and anxiety in family caregivers of patients with dementia: a randomized trial 
Trials  2013;14:305.
Dementia imposes a heavy burden on health and social care systems as well as on family caregivers who provide a substantial portion of the care. Interventions that effectively support caregivers may prevent or delay patient institutionalization and hence be cost-effective. However, evidence about the cost-effectiveness of such interventions is scarce. The aim of this study was to evaluate the cost-effectiveness of a family meetings intervention for family caregivers of dementia patients in comparison with usual care over a period of 12 months.
The economic evaluation was conducted from a societal perspective alongside a randomized trial of 192 primary caregivers with community-dwelling dementia patients. Outcome measures included the Quality Adjusted Life-Years (QALY) of caregivers and patients and the incidence of depression and anxiety disorders in caregivers. Missing cost and effect data were imputed using multiple imputations. Bootstrapping was used to estimate uncertainty around the cost-differences and the incremental cost-effectiveness ratio (ICER). The bootstrapped cost-effect pairs were plotted on a cost-effectiveness plane and used to estimate cost-effectiveness curves.
No significant differences in costs and effects between the groups were found. At 12 months, total costs per patient and primary caregiver dyad were substantial: €77,832 for the intervention group and €75,201 for the usual care group (adjusted mean difference per dyad €4,149, 95% CI -13,371 to 21,956, ICER 157,534). The main cost driver was informal care (66% of total costs), followed by patients’ day treatment and costs of hospital and long-term care facility admissions (23%). Based on the cost-effectiveness acceptability curves, the maximum probability that the intervention was considered cost-effective in comparison with usual care reached 0.4 for the outcome QALY per patient-caregiver dyad and 0.6 for the caregivers’ incidence of depression and/or anxiety disorders regardless of the willingness to pay.
The annual costs of caring for a person with dementia were substantial with informal care being by far the largest contributor to the total societal costs. Based on this study, family meetings cannot be considered a cost-effective intervention strategy in comparison with usual care.
Trial registration
ISRCTN register, ISRCTN90163486
PMCID: PMC3849827  PMID: 24053631
Caregivers; Cost-effectiveness; Dementia; Family meetings; Informal care
17.  Correction: Single-Subject Grey Matter Graphs in Alzheimer's Disease 
PLoS ONE  2013;8(9):10.1371/annotation/6a2e6405-ce1d-49e0-a88c-0017c680d597.
PMCID: PMC3796629  PMID: 24137511
18.  No evidence for additional blood–brain barrier P-glycoprotein dysfunction in Alzheimer's disease patients with microbleeds 
Decreased blood–brain barrier P-glycoprotein (Pgp) function has been shown in Alzheimer's disease (AD) patients using positron emission tomography (PET) with the radiotracer (R)-[11C]verapamil. Decreased Pgp function has also been hypothesized to promote cerebral amyloid angiopathy (CAA) development. Here, we used PET and (R)-[11C]verapamil to assess Pgp function in eighteen AD patients, of which six had microbleeds (MBs), presumably reflecting underlying CAA. No differences were found in binding potential and nonspecific volume of distribution of (R)-[11C]verapamil between patient groups. These results provide no evidence for additional Pgp dysfunction in AD patients with MBs.
PMCID: PMC3421102  PMID: 22588188
Alzheimer's disease; blood–brain barrier; cerebral amyloid angiopathy; P-glycoprotein; positron emission tomography; (R)-[11C]verapamil
20.  Injury markers predict time to dementia in subjects with MCI and amyloid pathology 
Neurology  2012;79(17):1809-1816.
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.
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 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.
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.
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.
PMCID: PMC3475623  PMID: 23019259
21.  Single-Subject Grey Matter Graphs in Alzheimer's Disease 
PLoS ONE  2013;8(3):e58921.
Coordinated patterns of cortical morphology have been described as structural graphs and previous research has demonstrated that properties of such graphs are altered in Alzheimer's disease (AD). However, it remains unknown how these alterations are related to cognitive deficits in individuals, as such graphs are restricted to group-level analysis. In the present study we investigated this question in single-subject grey matter networks. This new method extracts large-scale structural graphs where nodes represent small cortical regions that are connected by edges when they show statistical similarity. Using this method, unweighted and undirected networks were extracted from T1 weighted structural magnetic resonance imaging scans of 38 AD patients (19 female, average age 72±4 years) and 38 controls (19 females, average age 72±4 years). Group comparisons of standard graph properties were performed after correcting for grey matter volumetric measurements and were correlated to scores of general cognitive functioning. AD networks were characterised by a more random topology as indicated by a decreased small world coefficient (p = 3.53×10−5), decreased normalized clustering coefficient (p = 7.25×10−6) and decreased normalized path length (p = 1.91×10−7). Reduced normalized path length explained significantly (p = 0.004) more variance in measurements of general cognitive decline (32%) in comparison to volumetric measurements (9%). Altered path length of the parahippocampal gyrus, hippocampus, fusiform gyrus and precuneus showed the strongest relationship with cognitive decline. The present results suggest that single-subject grey matter graphs provide a concise quantification of cortical structure that has clinical value, which might be of particular importance for disease prognosis. These findings contribute to a better understanding of structural alterations and cognitive dysfunction in AD.
PMCID: PMC3594199  PMID: 23536835
22.  Clinical Symptoms and Risk Factors in Cerebral Microangiopathy Patients 
PLoS ONE  2013;8(2):e53455.
Although the clinical manifestation and risk factors of cerebral microangiopathy (CM) remain unclear, the number of diagnoses is increasing. Hence, patterns of association among lesion topography and severity, clinical symptoms and demographic and disease risk factors were investigated retrospectively in a cohort of CM patients.
Patients treated at the Department of Neurology, University of Bonn for CM (n = 223; 98m, 125f; aged 77.32±9.09) from 2005 to 2010 were retrospectively enrolled. Clinical symptoms, blood chemistry, potential risk factors, demographic data and ratings of vascular pathology in the brain based on the Wahlund scale were analyzed using Pearson's chi square test and one-way ANOVA.
Progressive cognitive decline (38.1%), gait apraxia (27.8%), stroke-related symptoms and seizures (24.2%), TIA-symptoms (22%) and vertigo (17%) were frequent symptoms within the study population. Frontal lobe WMLs/lacunar infarcts led to more frequent presentation of progressive cognitive decline, seizures, gait apraxia, stroke-related symptoms, TIA, vertigo and incontinence. Parietooccipital WMLs/lacunar infarcts were related to higher frequencies of TIA, seizures and incontinence. Basal ganglia WMLs/lacunar infarcts were seen in patients with more complaints of gait apraxia, vertigo and incontinence. Age (p = .012), arterial hypertension (p<.000), obesity (p<.000) and cerebral macroangiopathy (p = .018) were positively related to cerebral lesion load. For increased glucose level, homocysteine, CRP and D-Dimers there was no association.
This underlines the association of CM with neurological symptoms upon admission in a topographical manner. Seizures and vertigo are symptoms of CM which may have been missed in previous studies. In addition to confirming known risk factors such as aging and arterial hypertension, obesity appears to increase the risk as well. Since the incidence of CM is increasing, future studies should focus on the importance of prevention of vascular risk factors on its pathogenesis.
PMCID: PMC3564848  PMID: 23393549
23.  Integrative EEG biomarkers predict progression to Alzheimer's disease at the MCI stage 
Alzheimer's disease (AD) is a devastating disorder of increasing prevalence in modern society. Mild cognitive impairment (MCI) is considered a transitional stage between normal aging and AD; however, not all subjects with MCI progress to AD. Prediction of conversion to AD at an early stage would enable an earlier, and potentially more effective, treatment of AD. Electroencephalography (EEG) biomarkers would provide a non-invasive and relatively cheap screening tool to predict conversion to AD; however, traditional EEG biomarkers have not been considered accurate enough to be useful in clinical practice. Here, we aim to combine the information from multiple EEG biomarkers into a diagnostic classification index in order to improve the accuracy of predicting conversion from MCI to AD within a 2-year period. We followed 86 patients initially diagnosed with MCI for 2 years during which 25 patients converted to AD. We show that multiple EEG biomarkers mainly related to activity in the beta-frequency range (13–30 Hz) can predict conversion from MCI to AD. Importantly, by integrating six EEG biomarkers into a diagnostic index using logistic regression the prediction improved compared with the classification using the individual biomarkers, with a sensitivity of 88% and specificity of 82%, compared with a sensitivity of 64% and specificity of 62% of the best individual biomarker in this index. In order to identify this diagnostic index we developed a data mining approach implemented in the Neurophysiological Biomarker Toolbox ( We suggest that this approach can be used to identify optimal combinations of biomarkers (integrative biomarkers) also in other modalities. Potentially, these integrative biomarkers could be more sensitive to disease progression and response to therapeutic intervention.
PMCID: PMC3789214  PMID: 24106478
Neurophysiological Biomarkers; Alzheimer's disease; mild cognitive impairment (MCI); electroencephalography; predictive analysis; time series analysis; eyes closed resting state
24.  Blood–brain barrier P-glycoprotein function in healthy subjects and Alzheimer's disease patients: effect of polymorphisms in the ABCB1 gene 
EJNMMI Research  2012;2:57.
P-glycoprotein is a blood–brain barrier efflux transporter involved in the clearance of amyloid-beta from the brain and, as such, might be involved in the pathogenesis of Alzheimer's disease. P-glycoprotein is encoded by the highly polymorphic ABCB1 gene. Single-nucleotide polymorphisms in the ABCB1 gene have been associated with altered P-glycoprotein expression and function. P-glycoprotein function at the blood–brain barrier can be quantified in vivo using the P-glycoprotein substrate tracer (R)-[11C]verapamil and positron emission tomography (PET). The purpose of this study was to assess the effects of C1236T, G2677T/A and C3435T single-nucleotide polymorphisms in ABCB1 on blood–brain barrier P-glycoprotein function in healthy subjects and patients with Alzheimer's disease.
Thirty-two healthy subjects and seventeen patients with Alzheimer's disease underwent 60-min dynamic (R)-[11C]verapamil PET scans. The binding potential of (R)-[11C]verapamil was assessed using a previously validated constrained two-tissue plasma input compartment model and used as outcome measure. DNA was isolated from frozen blood samples and C1236T, G2677T/A and C3435T single-nucleotide polymorphisms were amplified by polymerase chain reaction.
In healthy controls, binding potential did not differ between subjects without and with one or more T present in C1236T, G2677T and C3435T. In contrast, patients with Alzheimer's disease with one or more T in C1236T, G2677T and C3435T had significantly higher binding potential values than patients without a T. In addition, there was a relationship between binding potential and T dose in C1236T and G2677T.
In Alzheimer's disease patients, C1236T, G2677T/A and C3435T single-nucleotide polymorphisms may be related to changes in P-glycoprotein function at the blood–brain barrier. As such, genetic variations in ABCB1 might contribute to the progression of amyloid-beta deposition in the brain.
PMCID: PMC3483228  PMID: 23067778
Blood–brain barrier; P-glycoprotein; ABCB1; MDR1; Polymorphisms; (R)-[11C]verapamil; PET
25.  Activity Dependent Degeneration Explains Hub Vulnerability in Alzheimer's Disease 
PLoS Computational Biology  2012;8(8):e1002582.
Brain connectivity studies have revealed that highly connected ‘hub’ regions are particularly vulnerable to Alzheimer pathology: they show marked amyloid-β deposition at an early stage. Recently, excessive local neuronal activity has been shown to increase amyloid deposition. In this study we use a computational model to test the hypothesis that hub regions possess the highest level of activity and that hub vulnerability in Alzheimer's disease is due to this feature. Cortical brain regions were modeled as neural masses, each describing the average activity (spike density and spectral power) of a large number of interconnected excitatory and inhibitory neurons. The large-scale network consisted of 78 neural masses, connected according to a human DTI-based cortical topology. Spike density and spectral power were positively correlated with structural and functional node degrees, confirming the high activity of hub regions, also offering a possible explanation for high resting state Default Mode Network activity. ‘Activity dependent degeneration’ (ADD) was simulated by lowering synaptic strength as a function of the spike density of the main excitatory neurons, and compared to random degeneration. Resulting structural and functional network changes were assessed with graph theoretical analysis. Effects of ADD included oscillatory slowing, loss of spectral power and long-range synchronization, hub vulnerability, and disrupted functional network topology. Observed transient increases in spike density and functional connectivity match reports in Mild Cognitive Impairment (MCI) patients, and may not be compensatory but pathological. In conclusion, the assumption of excessive neuronal activity leading to degeneration provides a possible explanation for hub vulnerability in Alzheimer's disease, supported by the observed relation between connectivity and activity and the reproduction of several neurophysiologic hallmarks. The insight that neuronal activity might play a causal role in Alzheimer's disease can have implications for early detection and interventional strategies.
Author Summary
An intriguing recent observation is that deposition of the amyloid-β protein, one of the hallmarks of Alzheimer's disease, mainly occurs in brain regions that are highly connected to other regions. To test the hypothesis that these ‘hub’ regions are more vulnerable due to a higher neuronal activity level, we examined the relation between brain connectivity and activity in a computational model of the human brain. Furthermore, we simulated progressive damage to brain regions based on their level of activity, and investigated its effect on the structure and dynamics of the remaining brain network. We show that brain hub regions are indeed the most active ones, and that by damaging networks according to regional activity levels, we can reproduce not only hub vulnerability but a range of phenomena encountered in actual neurophysiological data of Alzheimer patients as well: loss and slowing of brain activity in Alzheimer, loss of synchronization between areas, and similar changes in functional network organization. The results of this study suggest that excessive, connectivity dependent neuronal activity plays a role in the development of Alzheimer, and that the further investigation of factors regulating regional brain activity might help detect, elucidate and counter the disease mechanism.
PMCID: PMC3420961  PMID: 22915996

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