Alzheimer Disease: Scheltens P

van Dijk KR, Scheltens P, Luijpen MW, Sergeant JA, Scherder EJ. · Department of Clinical Neuropsychology, Vrije Universiteit, Amsterdam, The Netherlands. · Dement Geriatr Cogn Disord. · Pubmed #15802911 No free full text.

Abstract: In a number of studies, peripheral electrical nerve stimulation has been applied to Alzheimer's disease (AD) patients who lived in a nursing home. Improvements were observed in memory, verbal fluency, affective behavior, activities of daily living and on the rest-activity rhythm and pupillary light reflex. The aim of the present, randomized, placebo-controlled, parallel-group clinical trial was to examine the effects of electrical stimulation on cognition and behavior in AD patients who still live at home. Repeated measures analyses of variance revealed no effects of the intervention in the verum group (n = 32) compared with the placebo group (n = 30) on any of the cognitive and behavioral outcome measures. However, the majority of the patients and the caregivers evaluated the treatment procedure positively, and applying the daily treatment at home caused minimal burden. The lack of treatment effects calls for reconsideration of electrical stimulation as a symptomatic treatment in AD.

Meeter M, Kollen A, Scheltens P. · Department of Cognitive Psychology, Vrije Universiteit Amsterdam, NL 1081 BT Amsterdam, The Netherlands. · J Int Neuropsychol Soc. · Pubmed #15686607 No free full text.

Abstract: Patients with mild to moderate Alzheimer's disease and normal controls were tested on a retrograde amnesia test with semantic content (Neologism and Vocabulary Test, or NVT), consisting of neologisms to be defined. Patients showed a decrement as compared to normal controls, pointing to retrograde amnesia within semantic memory. No evidence for a gradient within this amnesia was found, although one was present on an autobiographic test of retrograde amnesia that had a wider time scale. Several explanations for these results are presented, including one that suggests that extended retrograde amnesia and semantic memory deficits are in fact one and the same deficit.

Goekoop R, Rombouts SA, Jonker C, Hibbel A, Knol DL, Truyen L, Barkhof F, Scheltens P. · Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands. · Neuroimage. · Pubmed #15589109 No free full text.

Abstract: Mild cognitive impairment (MCI) often represents an early form of Alzheimer disease (AD). In both MCI and AD, characteristic cholinergic changes may occur. Functional magnetic resonance imaging (fMRI) may help to examine neurochemical changes in early disease by studying signal reactivity to pharmacological challenge. In this study, MCI patients [n=28; mean age 73.6+/-7.5; mini mental state examination (MMSE) 27.0+/-1.2] were scanned during task performance in a randomized trial under three different medication regimes: at baseline [BL; no galantamine (GAL)], after a single oral dose of GAL (SD), and after prolonged exposure (steady state: SS). Memory tasks included an episodic face-encoding task and a parametric n-letter back working memory (WM) task. Alterations in brain activation patterns before and after treatment were analyzed for both tasks using multilevel statistical analysis. Significant increases in brain activation from BL were observed after prolonged exposure only. For face encoding (n=28), these involved left prefrontal areas, the anterior cingulate gyrus, left occipital areas, and left posterior hippocampus. For working memory (n=28), increased activation was found in right precuneus and right middle frontal gyrus, coinciding with increased accuracy scores after GAL treatment. In conclusion, cholinergic challenge produces alterations in brain activation patterns in elderly MCI patients that can be detected with fMRI. This should encourage further functional imaging studies to examine the status of neurotransmitter systems in disease.

Karas GB, Scheltens P, Rombouts SA, Visser PJ, van Schijndel RA, Fox NC, Barkhof F. · Department of Diagnostic Radiology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. · Neuroimage. · Pubmed #15488420 No free full text.

Abstract: PURPOSE: Mild cognitive impairment (MCI) is thought to be the prodromal phase to Alzheimer's disease (AD). We analyzed patterns of gray matter (GM) loss to examine what characterizes MCI and what determines the difference with AD. MATERIALS AND METHODS: Thirty-three subjects with AD, 14 normal elderly controls (NCLR), and 22 amnestic MCI subjects were included and underwent brain MR imaging. Global GM volume was assessed using segmentation and local GM volume was assessed using voxel-based morphometry (VBM); VBM was optimized for template mismatch and statistical mass. RESULTS: AD subjects had significantly (12.3%) lower mean global GM volume when compared to controls (517 +/- 58 vs. 590 +/- 52 ml; P < 0.001). Global GM volume in the MCI group (552 +/- 52) was intermediate between these two: 6.2% lower than AD and 6.5% higher than the controls but not significantly different from either group. VBM showed that subjects with MCI had significant local reductions in gray matter in the medial temporal lobe (MTL), the insula, and thalamus compared to NCLR subjects. By contrast, when compared to subjects with AD, MCI subjects had more GM in the parietal association areas and the anterior and the posterior cingulate. CONCLUSION: GM loss in the MTL characterizes MCI, while GM loss in the parietal and cingulate cortices might be a feature of AD.

Feldman H, Scheltens P, Scarpini E, Hermann N, Mesenbrink P, Mancione L, Tekin S, Lane R, Ferris S. · Division of Neurology, University of British Columbia, Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia, Canada. · Neurology. · Pubmed #15079026 No free full text.

Abstract: The authors investigated neuropsychiatric symptoms in mild cognitive impairment (MCI) from baseline data of the Investigation in the Delay to Diagnosis of AD with Exelon (InDDEx) study (n = 1,010). Neuropsychiatric symptoms were reported in 59% of subjects (Neuropsychiatric Inventory [NPI]). NPI+ subjects had significantly greater impairment on global, cognitive, and functional scores than NPI- subjects. The presence of neuropsychiatric symptoms appears to be a marker of MCI severity.

Karas GB, Burton EJ, Rombouts SA, van Schijndel RA, O'Brien JT, Scheltens P, McKeith IG, Williams D, Ballard C, Barkhof F. · Department of Diagnostic Radiology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. · Neuroimage. · Pubmed #12725765 No free full text.

Abstract: Voxel-based morphometry (VBM) has already been applied to MRI scans of patients with Alzheimer's disease (AD). The results of these studies demonstrated atrophy of the hippocampus, temporal pole, and insula, but did not describe any global brain changes or atrophy of deep cerebral structures. We propose an optimized VBM method, which accounts for these shortcomings. Additional processing steps are incorporated in the method, to ensure that the whole spectrum of brain atrophy is visualized. A local group template was created to avoid registration bias, morphological opening was performed to eliminate cerebrospinal fluid voxel misclassifications, and volume preserving modulation was used to correct for local volume changes. Group differences were assessed and thresholded at P < 0.05 (corrected). Our results confirm earlier findings, but additionally we demonstrate global cortical atrophy with sparing of the sensorimotor cortex, occipital poles, and cerebellum. Moreover, we show atrophy of the caudate head nuclei and medial thalami. Our findings are in full agreement with the established neuropathological descriptions, offering a comprehensive view of atrophy patterns in AD.

Stam CJ, van Cappellen van Walsum AM, Pijnenburg YA, Berendse HW, de Munck JC, Scheltens P, van Dijk BW. · Department of Clinical Neurophysiology, VU University Medical Centre, Amsterdam, The Netherlands. · J Clin Neurophysiol. · Pubmed #12488788 No free full text.

Abstract: The purpose of this study was to investigate interdependencies in whole-head magnetoencephalography (MEG) of Alzheimer patients and healthy control subjects. Magnetoencephalograms were recorded in 20 Alzheimer patients (11 men; mean age, 69.0 years [standard deviation, 8.2 years]); Mini-Mental State Examination score, 21.3 points; range, 15 to 27 points) and 20 healthy control subjects (9 men; mean age, 66.4 years [standard deviation, 9.0 years]) during a no-task eyes-closed condition with a 151 channel whole-head MEG system. Synchronization likelihood (a new measure for linear as well as nonlinear interdependencies between signals) and coherence were computed for each channel in different frequency bands (2 to 6, 6 to 10, 10 to 14, 14 to 18, 18 to 22, 22 to 40 Hz). Synchronization was lower in Alzheimer patients in the upper alpha band (10 to 14 Hz), the upper beta band (18 to 22 Hz), and the gamma band (22 to 40 Hz). In contrast, coherence did not show significant group differences at the p<0.05 level. The synchronization likelihood showed a spatial pattern (high synchronization central, parietal and right frontal; low synchronization, occipital and temporal). This study confirms a widespread loss of functional interactions in the alpha and beta bands, and provides the first evidence for loss of gamma band synchronization in Alzheimer's disease. Synchronization likelihood may be more sensitive to detect such changes than the commonly used coherence analysis.

Burton EJ, Karas G, Paling SM, Barber R, Williams ED, Ballard CG, McKeith IG, Scheltens P, Barkhof F, O'Brien JT. · Institute for Ageing and Health, University of Newcastle upon Tyne, United Kingdom. · Neuroimage. · Pubmed #12377138 No free full text.

Abstract: Previous cross-sectional MRI studies based on region-of-interest analyses have shown that increased cerebral atrophy is a feature of both Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Relative preservation of the hippocampus and temporal lobe structures in DLB compared to AD has been reported in region-of-interest-based studies. Recently, image processing techniques such as voxel-based morphometry (VBM) have been developed to provide an unbiased, visually informative, and comprehensive means of studying patterns of cerebral atrophy. We report the first study to use the voxel-based approach to assess patterns of cerebral atrophy in DLB compared to control subjects and AD. Regional gray matter volume loss was observed bilaterally in the temporal and frontal lobes and insular cortex of patients with DLB compared to control subjects. Comparison of dementia groups showed preservation of the medial temporal lobe, hippocampus, and amygdala in DLB relative to AD. Significant gray matter loss was also observed in the thalamus of AD patients compared to DLB.

Visser PJ, Verhey FR, Scheltens P, Cruts M, Ponds RW, Van Broeckhoven CL, Jolles J. · Department of Psychiatry and Neuropsychology, Institute of Brain and Behaviour, University of Maastricht, The Netherlands. · J Neurol. · Pubmed #11993532 No free full text.

Abstract: The Preclinical AD Scale (PAS) is a newly developed scale for the diagnosis of preclinical Alzheimer's disease (AD). The PAS combines six markers of preclinical AD, namely age, MMSE score, functional impairment, cognitive test performance, medial temporal lobe atrophy, and the apolipoprotein E (APOE) genotype. The aim of the study was to investigate whether the PAS can accurately identify subjects with preclinical AD who become demented during a 2 or 5 year follow-up from among subjects with mild cognitive impairment for other reasons. We also investigated whether a step-wise scoring of the PAS could reduce the number of elaborate or expensive diagnostic procedures. The PAS was scored retrospectively in two independent samples of non-demented subjects with mild cognitive impairment older than 55 years (average age 65.6 years), who were selected from a memory clinic population. In the first sample, the follow-up was 5 years (5-year follow-up sample; n=69). In the second sample, the follow-up was 2 years (2-year follow-up sample; n=23). The PAS item medial temporal lobe atrophy was not scored in the 5-year follow-up sample. A PAS cut-off score of 4/5 could best identify subjects with AD-type dementia at follow-up (n=25) in the 5-year follow-up sample with a sensitivity of 80% and a positive predictive value of 77%. A PAS cut-off score of 5/6 could best identify subjects with AD-type dementia at follow-up (n=8) in the 2-year follow-up sample with a sensitivity of 88% and a positive predictive value of 70%. The positive predictive value could be increased to 94% in the 5-year follow-up sample and to 80% in the 2-year follow-up sample by using higher cut-off scores, but this reduced the sensitivity. Step-wise scoring of the PAS had the same diagnostic accuracy as the total PAS score and reduced the number of cognitive assessments by 22 to 38%, the number of assessments of medial temporal lobe atrophy by 57 to 74%, and the number of APOE genotypings by 74%. It is concluded that the PAS is a useful scale to identify subjects with preclinical AD who will become demented during the next 2 or 5 years. Step-wise scoring of the PAS can reduce the number of elaborate or expensive diagnostic procedures considerably.

Bokde AL, Teipel SJ, Zebuhr Y, Leinsinger G, Gootjes L, Schwarz R, Buerger K, Scheltens P, Moeller HJ, Hampel H. · Dementia and Neuroimaging Section, Department of Psychiatry, Ludwig-Maximilian University, Nussbaumstr. 7, 80336, Munich, Germany. · J Neurol Sci. · Pubmed #11809164 No free full text.

Abstract: BACKGROUND: Neurodegenerative and cerebrovascular diseases show a distinct distribution of regional atrophy and subcortical lesions. OBJECTIVE: To develop an easily applicable landmark-based method for segmentation of the brain into the four cerebral lobes from MRI images. METHOD: The segmentation method relies on a combination of anatomical landmarks and geometrical definitions. It is applied on the surface reconstruction of the MRI volume. The internal borders between the lobes are defined on the axial slices of the brain. The reliability of this method was determined from MRI scans of 10 subjects. To illustrate the use of the method, it was applied to MRI scans of an independent group of 10 healthy elderly subjects and 10 patients with vascular dementia to determine the regional distribution of white matter hyperintensities (WMH). RESULTS: The intra-rater relative error (and intra-class correlation coefficient) of the lobe segmentation ranged from 1.6% to 6.9% (from 0.91 to 0.99). The inter-rater relative error (and intra-class correlation coefficient) ranged from 1.4% to 5.2% (from 0.96 to 0.99). Density of WMH was significantly higher in all four lobes in VD patients compared to controls (p<0.05). Within each group, WMH density was significantly higher in frontal and parietal than in temporal and occipital lobes (p<0.05). CONCLUSION: This landmark based method can accommodate age and disease-related changes in brain morphology. It may be particularly useful for the study of neurodegenerative and cerebrovascular disease and for the validation of template-based automated techniques.

Van Gool WA, Weinstein HC, Scheltens P, Walstra GJ, Scheltens PK. · Department of Neurology, Academic Medical Centre, PO Box 22700, 1100 DE, Amsterdam, Netherlands. · Lancet. · Pubmed #11513909 No free full text.

Abstract: BACKGROUND: Results of epidemiological studies, neuropathological observations, and in-vitro experiments all suggest that inflammatory mechanisms contribute to the destructive lesions in Alzheimer's disease. We aimed to establish the effect of the anti-inflammatory drug hydroxychloroquine on the progression of dementia. METHODS: We did a double-blind, parallel-group, multicentre trial in which we randomly assigned 168 patients with early Alzheimer's disease to hydroxychloroquine (200 or 400 mg dependent on bodyweight), or placebo for 18 months. Outcome measures were related to activities of daily living, cognitive function, and behavioural abnormalities. Analysis was by intention to treat. RESULTS: At 18 months, mean scores for the interview for deterioration in daily life in dementia in patients on hydroxychloroquine (22.6 [SD 11.4]) did not differ from those for patients on placebo (21.3 [10.5]). Also, mean scores on the cognitive subscale of the Alzheimer's disease assessment scale were closely similar in hydroxychloroquine (26.4 [14.9]) and placebo (25.7 [14.3]) treated patients, as were behavioural changes, measured by the revised memory and behavioural problems checklist (36.3 [12.0] and 34.2 [12.4], respectively). Explorative analyses did not suggest any specific subgroup that benefited from hydroxychloroquine. The frequency and nature of serious adverse events and side-effects were much the same in both groups. 155 (92%) patients completed all assessments over the entire study. INTERPRETATION: Anti-inflammatory treatment with hydroxychloroquine for 18 months does not slow the rate of decline in minimal or mild Alzheimer's disease.

Scheltens P, Kittner B. · Department of Neurology, Academisch Ziekenhuis VU, The Netherlands. · Ann N Y Acad Sci. · Pubmed #10818550 No free full text.

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Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka SK, van der Flier WM, Blankenstein MA, Ewers M, Rich K, Kaiser E, Verbeek M, Tsolaki M, Mulugeta E, Rosén E, Aarsland D, Visser PJ, Schröder J, Marcusson J, de Leon M, Hampel H, Scheltens P, Pirttilä T, Wallin A, Jönhagen ME, Minthon L, Winblad B, Blennow K. · Institute of Neuroscience and Physiology, Department of Neurochemistry and Psychiatry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden. · JAMA. · Pubmed #19622817 No free full text.

Abstract: CONTEXT: Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. OBJECTIVE: To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. DESIGN, SETTING, AND PARTICIPANTS: The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD. RESULTS: During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. CONCLUSIONS: This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.

Scheltens P. · Dept Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, the Netherlands. · Dialogues Clin Neurosci. · Pubmed #19585954 No free full text.

Abstract: Neuroimaging in the early differential diagnosis of dementia has gained considerable interest over the last decade. From being used for exclusive purposes only, neuroimaging is now in the forefront of aiding in the diagnosis of Alzheimer's disease (AD), frontotemporal dementia, vascular dementia, and and dementia with Lewy bodies (DLB). With the exception of dopamine transporter single photon-emission computed tomography imaging in DLB, imaging has not yet been incorporated into the diagnostic criteria for the various dementia syndromes, but that will soon change. The recently formulated research criteria for early AD recently formulated by Dubois et al explicitly mention magnetic resonance imaging and positron emission tomography for AD, and are an example of a new diagnostic process developing. In this review, the various imaging techniques will be highlighted, with an emphasis on their ability to diagnose Alzheimer's disease and separate it from other entities.

Visser PJ, Verhey F, Knol DL, Scheltens P, Wahlund LO, Freund-Levi Y, Tsolaki M, Minthon L, Wallin AK, Hampel H, Bürger K, Pirttila T, Soininen H, Rikkert MO, Verbeek MM, Spiru L, Blennow K. · Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, University of Maastricht, 6200 MD Maastricht, Netherlands. · Lancet Neurol. · Pubmed #19523877 No free full text.

Abstract: BACKGROUND: Alzheimer's disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group. METHODS: Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia. FINDINGS: The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4). INTERPRETATION: AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up. FUNDING: European Commission; Ana Aslan International Foundation.

Verwey NA, van der Flier WM, Blennow K, Clark C, Sokolow S, De Deyn PP, Galasko D, Hampel H, Hartmann T, Kapaki E, Lannfelt L, Mehta PD, Parnetti L, Petzold A, Pirttila T, Saleh L, Skinningsrud A, Swieten JC, Verbeek MM, Wiltfang J, Younkin S, Scheltens P, Blankenstein MA. · Department of Clinical Chemistry, VU University Medical Center, , HV, The Netherlands. · Ann Clin Biochem. · Pubmed #19342441 No free full text.

Abstract: BACKGROUND: Different cerebrospinal fluid (CSF) amyloid-beta 1-42 (Abeta(1-42)), total Tau (Tau) and Tau phosphorylated at threonine 181 (P-Tau) levels are reported, but currently there is a lack of quality control programmes. The aim of this study was to compare the measurements of these CSF biomarkers, between and within centres. METHODS: Three CSF-pool samples were distributed to 13 laboratories in 2004 and the same samples were again distributed to 18 laboratories in 2008. In 2004 six laboratories measured Abeta(1-42), Tau and P-Tau and seven laboratories measured one or two of these marker(s) by enzyme-linked immunosorbent assays (ELISAs). In 2008, 12 laboratories measured all three markers, three laboratories measured one or two marker(s) by ELISAs and three laboratories measured the markers by Luminex. RESULTS: In 2004, the ELISA intercentre coefficients of variance (interCV) were 31%, 21% and 13% for Abeta(1-42), Tau and P-Tau, respectively. These were 37%, 16% and 15%, respectively, in 2008. When we restricted the analysis to the Innotest (N = 13) for Abeta(1-42), lower interCV were calculated (22%). The centres that participated in both years (N = 9) showed interCVs of 21%, 15% and 9% and intra-centre coefficients (intraCV) of variance of 25%,18% and 7% in 2008. CONCLUSIONS: The highest variability was found for Abeta(1-42). The variabilities for Tau and P-Tau were lower in both years. The centres that participated in both years showed a high intraCV comparable to their interCV, indicating that there is not only a high variation between but also within centres. Besides a uniform standardization of (pre)analytical procedures, the same assay should be used to decrease the inter/intracentre variation.

van der Vlies AE, Verwey NA, Bouwman FH, Blankenstein MA, Klein M, Scheltens P, van der Flier WM. · Department of Neurology and Alzheimer Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · Neurology. · Pubmed #19307538 No free full text.

Abstract: OBJECTIVE: To investigate the relationship between CSF biomarkers and cognitive profiles in Alzheimer disease (AD). METHODS: We included 177 patients with AD. Digit Span, Visual Association Test (VAT), VAT object naming, Trail Making Test (TMT), and category fluency were used to assess cognitive functions. Disease severity was assessed using Mini-Mental State Examination; functional impairment was rated by Clinical Dementia Rating. In CSF, levels of amyloid-beta 1-42 (Abeta(1-42)), tau, and tau phosphorylated at threonine 181 (p-tau) were measured. K-means cluster analysis was performed with the three biomarkers to obtain three clusters. Multivariate analysis of variance for repeated measures was performed with CSF cluster as between-subjects factor, neuropsychological z scores as within-subjects variable, and age, sex, and education as covariates. RESULTS: Cluster 1 consisted of 88 patients (49%) with relatively high levels of Abeta(1-42) and low levels of tau and p-tau. Cluster 2 contained 72 patients (41%) with relatively low levels of Abeta(1-42) and high levels of tau and p-tau. Cluster 3 was made up of 17 patients (10%) with low levels of Abeta(1-42) and very high levels of tau and p-tau. No differences between clusters on age, sex, education, APOE genotype, disease duration, functional impairment, or disease severity were found. Patients in cluster 3 performed worse on VAT, TMT-A and -B, and fluency. CONCLUSIONS: Clusters of CSF biomarker levels are related to cognitive profiles in Alzheimer disease. A subgroup of patients with extremely high CSF levels of tau and tau phosphorylated at threonine 181 shows a distinct cognitive profile with more severe impairment of memory, mental speed, and executive functions, which cannot be explained by disease severity.

Henneman WJ, Sluimer JD, Barnes J, van der Flier WM, Sluimer IC, Fox NC, Scheltens P, Vrenken H, Barkhof F. · Department of Radiology, VU University Medical Center, Amsterdam, The Netherlands. · Neurology. · Pubmed #19289740 No free full text.

Abstract: OBJECTIVE: To investigate the added value of hippocampal atrophy rates over whole brain volume measurements on MRI in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and controls. METHODS: We included 64 patients with AD (67 +/- 9 years; F/M 38/26), 44 patients with MCI (71 +/- 6 years; 21/23), and 34 controls (67 +/- 9 years; 16/18). Two MR scans were performed (scan interval: 1.8 +/- 0.7 years; 1.0 T), using a coronal three-dimensional T1-weighted gradient echo sequence. At follow-up, 3 controls and 23 patients with MCI had progressed to AD. Hippocampi were manually delineated at baseline. Hippocampal atrophy rates were calculated using regional, nonlinear fluid registration. Whole brain baseline volumes and atrophy rates were determined using automated segmentation and registration tools. RESULTS: All MRI measures differed between groups (p < 0.005). For the distinction of MCI from controls, larger effect sizes of hippocampal measures were found compared to whole brain measures. Between MCI and AD, only whole brain atrophy rate differed significantly. Cox proportional hazards models (variables dichotomized by median) showed that within all patients without dementia, hippocampal baseline volume (hazard ratio [HR]: 5.7 [95% confidence interval: 1.5-22.2]), hippocampal atrophy rate (5.2 [1.9-14.3]), and whole brain atrophy rate (2.8 [1.1-7.2]) independently predicted progression to AD; the combination of low hippocampal volume and high atrophy rate yielded a HR of 61.1 (6.1-606.8). Within patients with MCI, only hippocampal baseline volume and atrophy rate predicted progression. CONCLUSION: Hippocampal measures, especially hippocampal atrophy rate, best discriminate mild cognitive impairment (MCI) from controls. Whole brain atrophy rate discriminates Alzheimer disease (AD) from MCI. Regional measures of hippocampal atrophy are the strongest predictors of progression to AD.

Kester MI, Blankenstein MA, Bouwman FH, van Elk EJ, Scheltens P, van der Flier WM. · Alzheimer Center and Department of Neurology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands. · J Alzheimers Dis. · Pubmed #19276554 No free full text.

Abstract: The object of this study was to elucidate the effect of age in the relationship between APOE genotype and CSF biomarkers amyloid-beta1-42 (Abeta42), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) in AD and controls. 302 AD patients and 174 controls were categorized into APOE epsilon4 carriers and non-carriers, and into younger and older (65years). In controls, older age and APOE epsilon4 were independently associated with lower Abeta42 and higher tau and ptau-181 levels (p < 0.05). For tau and ptau-181, there were also interactions (p < 0.10): older carriers had higher levels than older non-carriers, without effect for younger controls. In AD, APOE epsilon4 genotype had a main effect on Abeta42, but there was also an interaction: older carriers had lower Abeta42 than older non-carriers, without effect for younger AD patients (p < 0.05). For tau and ptau-181, there were only interactions: older carriers had higher levels than older non-carriers, while younger AD patients showed the opposite (p 0.05). Association between CSF biomarkers and APOE genotype were modified by age in both controls and AD patients. This suggests that cognitively healthy APOE epsilon4 carriers are more prone to develop AD pathology with aging. For AD patients, this provides support for the existence of subtypes within the disease.

Staekenborg SS, Koedam EL, Henneman WJ, Stokman P, Barkhof F, Scheltens P, van der Flier WM. · Department of Neurology, Alzheimer Center, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. · Stroke. · Pubmed #19228848 No free full text.

Abstract: BACKGROUND AND PURPOSE: We sought to determine the predictive value of magnetic resonance imaging measures of vascular disease (white matter hyperintensities [WMHs], lacunes, microbleeds, and infarcts) compared with atrophy on the progression of mild cognitive impairment to dementia. METHODS: We included 152 consecutive patients with mild cognitive impairment. Baseline magnetic resonance imaging was used to determine the presence of medial temporal lobe atrophy and vascular disease (presence of lacunes, microbleeds, and infarcts was determined, and WMHs were rated on a semiquantitative scale). Patients were followed up for 2+/-1 years. RESULTS: Seventy-two (47%) patients progressed to dementia during follow-up. Of these, 56 (37%) patients were diagnosed with Alzheimer's disease, and 16 (10%) patients were diagnosed with a non-Alzheimer dementia (including vascular dementia, frontotemporal lobar degeneration, and Parkinson dementia). Converters were older and had a lower Mini-Mental State Examination score at baseline. On baseline magnetic resonance imaging, patients who progressed to a non-Alzheimer dementia showed more severe WMHs and had a higher prevalence of lacunes in the basal ganglia and microbleeds compared with nonconverters. Cox proportional-hazard models showed that, adjusted for age and sex, baseline medial temporal lobe atrophy (hazard ratio=2.9; 95% CI, 1.7 to 5.3), but not vascular disease, was associated with progression to Alzheimer's disease. By contrast, deep WMHs (hazard ratio=5.7; 95% CI, 1.2 to 26.7) and periventricular hyperintensities (hazard ratio=6.5; 95% CI, 1.4 to 29.8) predicted progression to non-Alzheimer dementia. Furthermore, microbleeds (hazard ratio=2.6; 95% CI, 0.9 to 7.5) yielded a >2-fold increased, though nonsignificant, risk of non-Alzheimer dementia. CONCLUSIONS: Medial temporal lobe atrophy and markers of cerebrovascular disease predict the development of different types of dementia in mild cognitive impairment patients.

Zarei M, Damoiseaux JS, Morgese C, Beckmann CF, Smith SM, Matthews PM, Scheltens P, Rombouts SA, Barkhof F. · FMRIB Centre, University Oxford, Oxford, UK. · Stroke. · Pubmed #19164789 No free full text.

Abstract: BACKGROUND AND PURPOSE: Considerable clinical and radiological overlap between vascular dementia (VaD) and Alzheimer disease (AD) often makes the diagnosis difficult. Diffusion-tensor imaging studies showed that fractional anisotropy (FA) could be a useful marker for white matter changes. This study aimed to identify regional FA changes to identify a biomarker that could be used to differentiate VaD from AD. METHODS: T1-weighted and diffusion-tensor imaging scans were obtained in 13 VaD patients, 16 AD patients, and 22 healthy elderly controls. We used tract-based spatial statistics to study regional changes in fractional anisotropy in AD, VaD, and elderly controls. We then used probabilistic tractography to parcel the corpus callosum in 7 regions according to its connectivity with major cerebral cortices using diffusion-tensor imaging data set. We compared the volume and mean FA in each set of transcallosal fibers between groups using ANOVA and then applied a discriminant analysis based on FA and T2-weighted imaging measures. RESULTS: FA reduction in forceps minor was the most significant area of difference between AD and VaD. Segmentation of the corpus callosum using tractography and comparison of FA changes of each segment confirmed the FA changes in transcallosal prefrontal tracts of patients with VaD when compared to AD. The best discriminant model was the combination of transcallosal prefrontal FA and Fazekas score with 87.5% accuracy, 100% specificity, and 93% sensitivity (P<0.0001). CONCLUSIONS: Integrating mean FA in the forceps minor to the Fazekas score provides a useful quantitative marker for differentiating AD from VaD.

Montez T, Poil SS, Jones BF, Manshanden I, Verbunt JP, van Dijk BW, Brussaard AB, van Ooyen A, Stam CJ, Scheltens P, Linkenkaer-Hansen K. · Institute of Biophysics and Biomedical Engineering, Faculty of Sciences of the University of Lisbon, Campo Grande, 1749-016 Lisbon, Portugal. · Proc Natl Acad Sci U S A. · Pubmed #19164579 links to  free full text

Abstract: Encoding and retention of information in memory are associated with a sustained increase in the amplitude of neuronal oscillations for up to several seconds. We reasoned that coordination of oscillatory activity over time might be important for memory and, therefore, that the amplitude modulation of oscillations may be abnormal in Alzheimer disease (AD). To test this hypothesis, we measured magnetoencephalography (MEG) during eyes-closed rest in 19 patients diagnosed with early-stage AD and 16 age-matched control subjects and characterized the autocorrelation structure of ongoing oscillations using detrended fluctuation analysis and an analysis of the life- and waiting-time statistics of oscillation bursts. We found that Alzheimer's patients had a strongly reduced incidence of alpha-band oscillation bursts with long life- or waiting-times (< 1 s) over temporo-parietal regions and markedly weaker autocorrelations on long time scales (1-25 seconds). Interestingly, the life- and waiting-times of theta oscillations over medial prefrontal regions were greatly increased. Whereas both temporo-parietal alpha and medial prefrontal theta oscillations are associated with retrieval and retention of information, metabolic and structural deficits in early-stage AD are observed primarily in temporo-parietal areas, suggesting that the enhanced oscillations in medial prefrontal cortex reflect a compensatory mechanism. Together, our results suggest that amplitude modulation of neuronal oscillations is important for cognition and that indices of amplitude dynamics of oscillations may prove useful as neuroimaging biomarkers of early-stage AD.

Tolboom N, Yaqub M, van der Flier WM, Boellaard R, Luurtsema G, Windhorst AD, Barkhof F, Scheltens P, Lammertsma AA, van Berckel BN. · Department of Nuclear Medicine and PET Research, VU University Medical Centre, Amsterdam, The Netherlands. · J Nucl Med. · Pubmed #19164243 No free full text.

Abstract: 11C-Pittsburgh Compound-B (11C-PIB) and 18F-(2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) (18F-FDDNP) have been developed as PET tracers for in vivo imaging of pathology in Alzheimer's disease (AD). The purpose of this study was to directly compare these tracers in patients with AD, patients with mild cognitive impairment (MCI), and healthy controls. METHODS: Paired 11C-PIB and 18F-FDDNP scans were acquired in 14 patients with AD, 11 patients with amnestic MCI, and 13 controls. For both tracers, parametric images of binding potential (BPND) were generated. Global cortical BPND was assessed using ANOVA. In addition, regional patterns of BPND were compared between diagnostic groups using ANOVA for repeated measures. RESULTS: Global cortical BPND of 11C-PIB showed higher binding in patients with AD than in controls and patients with MCI. 18F-FDDNP uptake was higher in patients with AD than in controls, but MCI could not be distinguished from AD or from controls. Global BPND values of both tracers were moderately correlated (r=0.45; P=0.005). In MCI, BPND of 11C-PIB showed a bimodal distribution, whereas values for 18F-FDDNP were more widespread, with more MCI patients demonstrating increased uptake. Regional 11C-PIB binding showed different patterns across diagnostic groups, as AD patients showed an overall increase in binding, with the lowest binding in the medial temporal lobe. With 18F-FDDNP, patterns were similar across diagnostic groups. For all groups, highest values were observed in the medial temporal lobe. CONCLUSION: Differences in BPND between patients with AD, patients with MCI, and controls were more pronounced for 11C-PIB. The difference in regional binding, the moderate correlation, and the discrepant findings in MCI suggest that they measure related, but different, characteristics of the disease.

Henneman WJ, Sluimer JD, Cordonnier C, Baak MM, Scheltens P, Barkhof F, van der Flier WM. · Department of Radiology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands. · Stroke. · Pubmed #19109551 No free full text.

Abstract: BACKGROUND AND PURPOSE: MRI biomarkers play an important role in the diagnostic work-up of dementia, but their prognostic value is less well-understood. We investigated if simple MRI rating scales predict mortality in a memory clinic population. METHODS: We included 1138 consecutive patients attending our memory clinic. Diagnostic categories were: subjective complaints (n=220), mild cognitive impairment (n=160), Alzheimer disease (n=357), vascular dementia (n=46), other dementia (n=136), and other diagnosis (n=219). Baseline MRIs were assessed using visual rating scales for medial temporal lobe atrophy (range, 0-4), global cortical atrophy (range, 0-3), and white matter hyperintensities (range, 0-3). Number of microbleeds and presence of infarcts were recorded. Cox-regression models were used to calculate the risk of mortality. RESULTS: Mean follow-up duration was 2.6 (+/-1.9) years. In unadjusted models, all MRI markers except infarcts predicted mortality. After adjustment for age, sex, and diagnosis, white matter hyperintensities, and microbleeds predicted mortality (white matter hyperintensities: hazard ratio [HR], 1.2; 95% CI, 1.0-1.4; microbleeds: HR, 1.02 95% CI, 1.00-1.03; categorized: HR, 1.5; 95% CI, 1.1-2.0). The predictive effect of global cortical atrophy was restricted to younger subjects (HR, 1.7; 95% CI, 1.2-2.6). An interaction between microbleeds and global cortical atrophy indicated that mortality was especially high in patients with both microbleeds and global cortical atrophy. CONCLUSIONS: Simple MRI biomarkers, in addition to their diagnostic use, have a prognostic value with respect to mortality in a memory clinic population. Microbleeds were the strongest predictor of mortality.

Liedorp M, van der Flier WM, Hoogervorst EL, Scheltens P, Stam CJ. · Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands. · Dement Geriatr Cogn Disord. · Pubmed #19088474 No free full text.

Abstract: AIM: To describe associations of abnormalities in the electroencephalogram (EEG) with the most prevalent diagnoses in a memory clinic cohort. METHODS: Associations between visual EEG findings and diagnoses in 1,116 consecutive patients [382 Alzheimer's disease (AD), 274 subjective complaints, 190 mild cognitive impairment (MCI), 118 psychiatric disorder, 61 frontotemporal lobar degeneration, 53 vascular dementia (VaD), 38 dementia with Lewy bodies (DLB)] were determined by prevalence ratio (PR). RESULTS: Diagnoses of subjective complaints [PR = 1.6; 95% confidence interval (CI) = 1.4-1.9] and psychiatric disorder (1.4; 95% CI = 1.1-1.9) were associated with a normal EEG, while subjects with both focal and diffuse EEG disturbances were more likely to have DLB (3.5; 95% CI = 2.1-5.6), VaD (2.3; 95% CI = 1.4-3.6) or AD (1.5; 95% CI = 1.3-1.8). Subjects with only diffuse EEG abnormalities were more likely to have AD (PR = 1.5; 95% CI = 1.3-1.9). The prevalence of MCI was higher among those with only focal EEG abnormalities (PR = 1.3; 95% CI = 1.0-1.7). CONCLUSIONS: A normal EEG argues for subjective complaints or psychiatric diagnosis. An EEG with only focal abnormalities supports MCI. An EEG with only diffuse abnormalities argues for AD. An EEG with both focal and diffuse abnormalities argues for DLB, VaD or AD.