Alzheimer Disease: Knol DL

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.

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.

Pijnenburg YA, Schoonenboom SN, Barkhof F, Knol DL, Mulder C, Van Kamp GJ, Van Swieten JC, Scheltens P. · Alzheimer Center, Department of Neurology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · J Neurol Neurosurg Psychiatry. · Pubmed #16421130 links to  free full text

Abstract: In order to better understand the large variation in cerebrospinal fluid (CSF) tau and amyloid-beta(1-42) (Abeta42) in frontotemporal lobar degeneration (FTLD), relations between these biomarkers and clinical parameters, neuroimaging characteristics, and apolipoprotein E (ApoE) genotype were studied in 31 patients with FTLD, including 16 patients with the frontal variant and 15 with the temporal variant. CSF tau was highest in FTLD with predominant temporal involvement. In the frontal subgroup, CSF tau level was influenced by the number of ApoE epsilon3 alleles. In the temporal subgroup, CSF tau level was dependent on a combination of CSF Abeta42, age, disease duration, and disease severity. No relation with degree of atrophy or asymmetry on neuroimaging could be established. CSF Abeta42 variability remained unexplained. Future research could study the role of ApoE genotype and Abeta42 in FTLD, as well as establish measures for disease intensity.

Pijnenburg YA, v d Made Y, van Cappellen van Walsum AM, Knol DL, Scheltens P, Stam CJ. · Department of Neurology and Alzheimer Center, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. · Clin Neurophysiol. · Pubmed #15134700 No free full text.

Abstract: OBJECTIVE: Synchronization likelihood analysis of resting state EEG has shown that cognitive dysfunction in Alzheimer's disease (AD) and its precursor mild cognitive impairment (MCI) are associated with a loss of functional connectivity in high (upper alpha and beta) frequency bands. Working memory tasks are known to change functional connectivity, but it is unknown whether this increases the differences between AD, MCI and healthy controls. Our objective was to investigate the behavior of synchronization likelihood of multichannel EEG in AD, MCI and cognitively healthy controls, both at rest and during a working memory task. METHODS: EEGs (200 Hz sample frequency, 21 channels, average reference) were recorded at rest as well as during a visual working memory task in 14 patients with AD according to the NINCDS-ADRDA criteria (mean age 76.4; SD 13.6), 11 patients with MCI according to the criteria of Petersen (mean age 78.4; SD 6.4) and 14 with subjective memory complaints but no demonstrable memory disturbance (mean age 61.6; SD 26.6). The synchronization likelihood was computed over 19 channels, comparing each channel with all the other channels for the 0.5-4, 4-8, 8-10, 10-12, 12-30, 30-50 Hz frequency bands. RESULTS: The synchronization likelihood was significantly decreased in the upper alpha (10-12) and beta (12-30) bands in AD compared to persons with subjective memory complaints. The working memory task scores strongly correlated with Mini-Mental State Examination scores. During the working memory task the synchronization likelihood was significantly higher in MCI compared to the control subjects in the lower alpha band (8-10 Hz). CONCLUSIONS: Decrease of beta band synchronization occurs in mild AD, both in a resting condition and during a working memory task. SIGNIFICANCE: Decrease of beta band synchronization in mild AD is a robust finding. The present study confirms our findings in a different cohort of patients, using alternative frequency bands. The diagnostic value of the synchronization likelihood in AD and MCI needs to be further established.

van Straaten EC, Scheltens P, Knol DL, van Buchem MA, van Dijk EJ, Hofman PA, Karas G, Kjartansson O, de Leeuw FE, Prins ND, Schmidt R, Visser MC, Weinstein HC, Barkhof F. · Department of Neurology and Alzheimer Center, VU Medical Center, De Boelelaan 1117, PO Box 7057, 1007 MB Amsterdam, Netherlands. · Stroke. · Pubmed #12855825 links to  free full text

Abstract: BACKGROUND AND PURPOSE: Vascular dementia (VaD) is thought to be the most common cause of dementia after Alzheimer's disease. The commonly used International Workshop of the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) criteria for VaD necessitate evidence of vascular disease on CT or MRI of the brain. The purposes of our study were to operationalize the radiological part of the NINDS-AIREN criteria and to assess the effect of this operationalization on interobserver agreement. METHODS: Six experienced and 4 inexperienced observers rated a set of 40 MRI studies of patients with clinically suspected VaD twice using the NINDS-AIREN set of radiological criteria. After the first reading session, operational definitions were conceived, which were subsequently used in the second reading session. Interobserver reproducibility was measured by Cohen's kappa. RESULTS: Overall agreement at the first reading session was poor (kappa=0.29) and improved slightly after application of the additional definitions (kappa=0.38). Raters in the experienced group improved their agreement from almost moderate (kappa=0.39) to good (0.62). The inexperienced group started out with poor agreement (kappa=0.17) and did not improve (kappa=0.18). The experienced group improved in both the large- and small-vessel categories, whereas the inexperienced group improved generally in the extensive white matter hyperintensities categories. CONCLUSIONS: Considerable interobserver variability exists for the assessment of the radiological part of the NINDS-AIREN criteria. Use of operational definitions improves agreement but only for already experienced observers.

van Cappellen van Walsum AM, Pijnenburg YA, Berendse HW, van Dijk BW, Knol DL, Scheltens P, Stam CJ. · Department of Clinical Neurophysiology, VU University Medical Centre, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands. · Clin Neurophysiol. · Pubmed #12804672 No free full text.

Abstract: OBJECTIVE: A measure of neural complexity (C(N)) (Proc. Natl Acad. Sci. USA 91 (1994) 5033) was applied to magnetoencephalography (MEG) data to test the hypothesis that C(N) decreases when information processing in the brain is impaired, as is the case in patients with Alzheimer's Disease (AD). METHODS: One hundred and fifty-one channel MEGs were recorded in 20 AD patients and 20 healthy age-matched controls in a resting condition with eyes open (EO) and eyes closed (EC). Artifact-free epochs of 117 channels were selected for analysis. C(N) and D(2) were computed in different frequency bands, and correlated with the MMSE. RESULTS: The Group x Frequency band interaction was significant for both C(N) and D(2). C(N) was higher in AD, as compared with controls, in the 2-4 and 4-8Hz bands, and D(2) was higher in AD patients in the 14-20 and 20-30Hz bands. The C(N) was higher in the EC condition compared to the EO condition, whereas the D(2) was higher in the EO condition. CONCLUSIONS: The hypothesis of Tononi et al. (Proc. Natl Acad. Sci. USA 91 (1994) 5033) that the neural complexity decreases in AD patients has to be rejected. However, both neural complexity and the correlation dimension did show differences between controls and AD patients which depended on frequency band.