Mony deLeon

The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: Evidence of validity

An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance.

The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome

The gene encoding the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A (DYRK1A) is located in the Down syndrome (DS) critical region of chromosome 21. The third copy of DYRK1A is believed to contribute to abnormal brain development in patients with DS. In vitro studies showing that DYRK1A phosphorylates tau protein suggest that this kinase is also involved in tau protein phosphorylation in the human brain and contributes to neurofibrillary degeneration, and that this contribution might be enhanced in patients with DS. To explore this hypothesis, the brain tissue from 57 subjects including 16 control subjects, 21 patients with DS, and 20 patients with sporadic Alzheimer’s disease (AD) was examined with two antibodies to the amino-terminus of DYRK1A (7F3 and G-19), as well as two polyclonal antibodies to its carboxy-terminus (X1079 and 324446). Western blots demonstrated higher levels of full-length DYRK1A in the brains of patients with DS when compared to control brains. Immunocytochemistry revealed that DYRK1A accumulates in neurofibrillary tangles (NFTs) in subjects with sporadic AD and in subjects with DS/AD. Overexpression of DYRK1A in patients with DS was associated with an increase in DYRK1A-positive NFTs in a gene dosage-dependent manner. Results support the hypothesis that overexpressed DYRK1A contributes to neurofibrillary degeneration in DS more significantly than in subjects with two copies of the DYRK1A gene and sporadic AD. Immunoreactivity with antibodies against DYRK1A not only in NFTs but also in granules in granulovacuolar degeneration and in corpora amylacea suggests that DYRK1A is involved in all three forms of degeneration and that overexpression of this kinase may contribute to the early onset of these pathologies in DS.

Cell type- and brain structure-specific patterns of distribution of minibrain kinase in human brain

The minibrain kinase (Mnb/Dyrk1A) gene is localized in the Down syndrome (DS) critical region of chromosome 21. This gene encodes a proline-directed serine/threonine protein kinase (minibrain kinase-Mnb/Dyrk1A), which is required for the proliferation of distinct neuronal cell types during postembryonic neurogenesis. To study the distribution of Mnb/Dyrk1A during human brain development and aging, we raised Mnb/Dyrk1A-specific antibody (mAb 7F3) and examined 22 brains of normal subjects from 8 months to 90 years of age. We found that neurons were the only cells showing the presence of 7F3-positive product in both cell nucleus and cytoplasm. Nuclear localization supports the concept that Mnb/Dyrk1A may be involved in control of gene expression. Synaptic localization of Mnb/Dyrk1A also supports our previous studies suggesting that Mnb/Dyrk1A is a regulator of assembly of endocytic apparatus and appears to be involved in synaptic vesicle recycling and synaptic signal transmission. Accumulation of numerous 7F3-positive corpora amylacea in the memory and motor system subdivisions in subjects older than 33 years of age indicates that Mnb/Dyrk1A is colocalized with markers of astrocyte and neuron degeneration. Differences in the topography and the amount of Mnb/Dyrk1A in neurons, astrocytes, and ependymal and endothelial cells appear to reflect cell type- and brain structure-specific patterns in trafficking and utilization of Mnb/Dyrk1A.

Comparison of human septal nuclei MRI measurements using automated segmentation and a new manual protocol based on histology.

Septal nuclei, located in basal forebrain, are strongly connected with hippocampi and important in learning and memory, but have received limited research attention in human MRI studies. While probabilistic maps for estimating septal volume on MRI are now available, they have not been independently validated against manual tracing of MRI, typically considered the gold standard for delineating brain structures. We developed a protocol for manual tracing of the human septal region on MRI based on examination of neuroanatomical specimens. We applied this tracing protocol to T1 MRI scans (n=86) from subjects with temporal epilepsy and healthy controls to measure septal volume. To assess the inter-rater reliability of the protocol, a second tracer used the same protocol on 20 scans that were randomly selected from the 72 healthy controls. In addition to measuring septal volume, maximum septal thickness between the ventricles was measured and recorded. The same scans (n=86) were also analyzed using septal probabilistic maps and DARTEL toolbox in SPM. Results show that our manual tracing algorithm is reliable, and that septal volume measurements obtained via manual and automated methods correlate significantly with each other (p<.001). Both manual and automated methods detected significantly enlarged septal nuclei in patients with temporal lobe epilepsy in accord with a proposed compensatory neuroplastic process related to the strong connections between septal nuclei and hippocampi. Septal thickness, which was simple to measure with excellent inter-rater reliability, correlated well with both manual and automated septal volume, suggesting it could serve as an easy-to-measure surrogate for septal volume in future studies. Our results call attention to the important though understudied human septal region, confirm its enlargement in temporal lobe epilepsy, and provide a reliable new manual delineation protocol that will facilitate continued study of this critical region.

EFFECT OF OBSTRUCTIVE SLEEP APNEA (OSA) ON RATE OF CHANGE OF AD BIOMARKERS IN COGNITIVELY NORMAL, MCI AND AD ELDERLY: FINDINGS FROM THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI) COHORT

Background: Evidence from numerous research implicates disturbed sleep or lack of sleep as one of the risk factors for Alzheimer’s disease (AD) and in a recent meta-analysis, we confirmed the association providing an “average” magnitude of effect. However, the extent of the risk of the association of disturbed sleep with AD biomarkers remains uncertain. We conducted further subgroup meta-analyses to quantify the effect of disturbed sleep on cognitive impairment; preclinical AD and symptomatic AD respectively. Methods:PubMed, Embase, Web of Science, and the Cochrane library were used to identify original published literature for this review. Sleep problems and/or disorders were the risk factor of interest in this meta-analysis, and grouped as sleep quality, sleep duration, circadian rhythm abnormalities, insomnia, and obstructive sleep apnea (OSA) for sub-group analyses. Our target variables included the use of cognitive tests assessing cognitive impairment; the use of AD biomarkers or abnormal proteins assessing preclinical AD; and the use of ICD9/DSMIV diagnoses of symptomatic AD. Effect estimates of individual studies were pooled and relative risks (RR) and 95% confidence intervals (CI) were calculated using random effects models. Meta-regression analyses examining the effect of potential influencing factors was also conducted. Results:Twentyseven observational studies (n 1⁄4 69,216 participants) that provided 52 RR estimates were included in the meta-analysis. Subgroup meta-analytic findings showed a RR increase inverse to diagnostic confidence (e.g., 1.60, 1.70 and 3.80 for AD, Cognitive Impairment and preclinical AD, P-value <.001 for all). Relative risk for AD and/or cognitive decline was (RR: 2.37, 1.86, 1.62, 1.38 and 1.38, p<.001 for all) for OSA, sleep quantity, sleep quality, insomnia, and circadian rhythm abnormalities respectively. Meta-regression results suggested that sample size might have significantly influenced the effect size such that larger sample size studies tended to result in smaller risk and vice versa. Conclusions:Our findings suggest that disturbed sleep had a four-fold association with AD biomarkers. OSA also appeared to be a strong risk factor for AD. Since changes in AD biomarkers are predictive of persons that ultimately develop AD, these results highlight potential mechanistic relationships that are vital for potential prevention of AD.

CSF Alzheimer's disease-related biomarkers are higher in subjects with periodontal disease

cognitive performance in “normal” individuals may therefore provide evidence of disease progression. Using a cohort of aging cognitively intact individuals with a first-degree family history of AD, we evaluated performance in several cognitive domains in relation to AD biomarkers and APOEe4 status. Methods:Baseline data were acquired for an ongoing prevention trial nested in the PREVENT-AD program. After screening for cognitive disorder using the Montreal Cognitive Assessment and the Clinical Dementia Rating, we obtained neuropsychological performance measures using the Repeatable Battery for Assessment of Neuropsychologic Status (RBANS), which evaluates 5 cognitive domains (immediate memory, delayed memory, attention, language and visuospatial/ constructional) as well as global cognition. Cerebrospinal fluid (CSF) was obtained by lumbar puncture, and protein concentrations were measured using Innotest technology for tau, P-tau and Ab142, and using ELISA for apolipoprotein E.Results:Baseline RBANS scores were within the normal range for age and education but were lower in all domains in older subjects (n1⁄4235; p<0.0005). Higher levels of CSF tau, P-tau, apoE and tau/Ab1-42 ratio (n1⁄485) were associated with lower global cognitive performance and with lower scores in several domains. In APOEe4+ individuals (n1⁄428), tau and P-tau were inversely correlated with attention, delayed memory and global cognition. In the remainder (n1⁄457), we observed a relationship only with language (inverse correlation with tau, P-tau, and apoE) and attention scores (inverse correlation with Ab1-42 and ratio of tau/Ab1-42 (Ab r1⁄4 -0.3, p1⁄40.03; ratio r1⁄4-0.4, p1⁄40.02). Conclusions: Tau and P-tau, recognized biomarkers of neuronal injury, were associated with cognitive scores in a cognitively “normal” population at risk of AD. As expected, CSF amyloid was weakly related to cognition but, surprisingly, elevated CSF apoE protein was associated with reduced cognitive performance. Most such correlations were evident only in those with APOEe4. Especially in the latter group, the data suggest the presence of on ongoing silent disease process. Forthcoming longitudinal data should further elucidate the role of progressive pathophysiological processes in emerging clinical manifestations of disease.

SLEEP DISORDERED BREATHING AND BRAIN BETA-AMYLOID BOTH PREDICT TIME-TO-PROGRESSION FROM COGNITIVE NORMAL TO MILD COGNITIVE IMPAIRMENT WITH BRAIN BETA-AMYLOID MODIFYING THE PROGRESSION RISK

and maximally for protocol-3 at 17446687 mm. The linearregression between protocol-2-3 showed the strongest relationship (p< 0.001; r 1⁄4 0.92), while the relationship between “penumbra” volumes for Protocol-1-2 (p1⁄4 0.003; r1⁄4 0.68) and Protocol-1-3 (p 1⁄4 0.013; r 1⁄4 0.56) were less robust. In addition, protocol-3 appeared optimal for co-registration of diffusion tensor and arterial spin labeling imaging for the detection of pre-WMH pathologic changes within the “penumbra“. Conclusions: Reliable volumetric quantification methodologies are essential for the determination of longitudinal WMH change over a one-year period, amenable to use in future clinical trials of small vessel ischemic disease. Future work, validating our optimal WMH “penumbra” quantification protocol amenable to multi-site studies is underway currently.

CHALLENGES ASSOCIATED WITH BIOMARKER-BASED CLASSIFICATIONS SYSTEMS FOR ALZHEIMER’S DISEASE

Vera M. Mendes, Naomi De Roeck, Javier S aez-Valero, Eduard A. Struys, Kees WJ. van Uffelen, Eugeen Vanmechelen, Ulf Andreasson, Charlotte E. Teunissen, Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands; Institute Born-Bunge, Wilrijk, Belgium; Instituto de Neurociencias de Alicante, Universidad Miguel Hern andez-CSIC, Sant Joan d’Alacant, Spain; VUmc, Amsterdam, Netherlands; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Reference Center for Biological Markers of Dementia, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; VU University Medical Center, Amsterdam, Netherlands; VU University Medical Center Amsterdam, Amsterdam, Netherlands; Universidad Miguel Hern andez-CSIC, Alicante, Spain; University of Coimbra, Coimbra, Portugal; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Reference Center for Biological Markers of Dementia, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Instituto de Neurociencias de Alicante, Universidad Miguel Hern andez-CSIC, Sant Joan d’Alacant, Spain; Department of Biochemistry, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, Netherlands; ADx NeuroSciences NV, Technologiepark, Ghent, Belgium; Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, M€olndal, Sweden; Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: c.teunissen@vumc.nl

OBSTRUCTIVE SLEEP APNEA, BRAIN BETA-AMYLOID MEASURES AND TIME-TO-PROGRESSION FROM MILD COGNITIVE IMPAIRMENT TO ALZHEIMER’S DISEASE

Age, years, mean (SD) 76.7 (8.16) Female, n (%) 82 (51.9%) White, n (%) 124 (78.5%) Education, years, mean (SD) 17.2 (2.29) APOE e4+, n (%) 35 (27.1%) PiB+, n (%) 48 (30.4%) Clinical diagnosis, n (%) Cognitively normal 153 (96.8%) Mild cognitive impairment 3 (1.90%) Dementia 2 (1.27%) Follow-up duration, years, mean (SD) 2.50 (3.15) Individuals with: 1 visit, n (%) 71 (44.9%) 2 visits 35 (22.2%) 3 visits 20 (12.7%) 4 visits 11 (6.96%) 5 visits 10 (6.33%) 6-8 visits 11 (6.96%)

Effects of metabolic syndrome, antihypertensive medications, and statins on PiB deposition in cognitively normal subjects

on MMSE. The average age was 79.8 65.9 year old. The disease duration is 3.3 6 2.0 years. They are divided into two groups according to the specific binding ratio (SBR) of I-FP-CIT SPECT. The SBR is derived from a measure of total striatal count (TossiciBolt L et al, Eur J Nucl Med Mol Imaging 2006, 33:1491). The patients with less than 4.0 on the SBR were referred to the low DAT group (L-DAT, N1⁄4 11) and those with more than 4.0 were designated to the normal DAT group (N-DAT, N 1⁄4 8). A three-dimensional stereotactic surface projection (3D-SSP) analysis of SPECT was performed using the interface software iSSP5 and iSSP35_2tZ (Nihon Medi-Physics Corporation,Tokyo, Japan).We used Z-score 2 as a cut off value. Results: There was no significant difference of age, disease duration and score ofMMSE and UPDRS part III between L-DAT and N-DAT group. The left lateral and bilateral medial parietal lobe demonstrated decreased rCBF in the all patients examined compared with age-matched controls. When we compared rCBF SPECT between L-DAT and N-DAT group, L-DAT group showed lower rCBF in the bilateral medial frontal and medial parietal lobe than N-DAT group. Conclusions: Low rCBF in the medial prefrontal cortex may be helpful to differentiate DLB from AD.