Banner Sun Health Research Institute Research Articles

Increased Alzheimer’s Disease Neuropathology is Associated with Type 2 Diabetes and ApoE ε4 Carrier Status

Past studies investigating the association between Alzheimer's disease (AD) pathology and diabetes mellitus type 2 (DM2) have provided conflicting results. While several studies indicate that subjects with comorbid AD and DM2 have less AD pathology, others have found no significant differences in AD pathology between the two groups. Other studies have indicated that individuals with AD and DM2 have significantly greater neuropathology than AD individuals who do not have DM2. Additional research has demonstrated that ApoE ε4 carriers with AD and DM2 have significantly greater pathology than ApoE ε4 non-carriers. Data on clinically and pathologically diagnosed Alzheimer's disease cases (NINDS-ADRDA clinically and NIA Reagan intermediate or high pathologically) with DM2 (n= 40) and those without DM2 (n= 322) from the Banner Sun Health Research Institute Brain and Body Donation Program were obtained for this study. Plaque and tangle scores from the frontal, parietal, temporal, entorhinal and hippocampal regions were compared between the DM2+ and DM2 - groups. In addition, total plaque count, total tangle count, and Braak scores were also compared between groups. Similar analyses were conducted to determine the effect of ApoE ε4 carrier status on the neuropathological variables while also accounting for and DM2 status. The DM2+ and DM2 - groups showed no significant differences on plaque and tangle pathology. Logistic regression analyses, which accounted for the effects of ApoE .ε4 carrier status and age at death, found no association between total plaque [OR 1.05 (0.87, 1.27), p = 0.60] or total tangle [OR 0.97 (0.89, 1.07) p = 0.58] counts and DM2 status. ApoE ε4 carrier status was not significantly associated with DM2 status [.Χ2 = 0.30 (df = 1), p = 0.58]. Within the DM2+ group, significantly greater plaque and tangle pathology was found for ApoE ε4 carriers in relation to DM2+ ApoE ε4 non-carriers. Overall, the presence of DM2 does not affect plaque and tangle burden in a sample of clinically and pathologically confirmed AD cases. Among AD individuals with DM2, those who are ApoE ε4 carriers had significantly greater neuropathology than those who do not carry an ApoE ε4 allele. Positive DM2 status appears to exacerbate AD neuropathology in the presence of ApoE ε4.

Lab Testing in Diagnosis of Alzheimer’s Disease: An Update

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessLab Testing in Diagnosis of Alzheimer’s Disease: An UpdateSandra Jacobson, M.D.Sandra JacobsonSearch for more papers by this author, M.D.Published Online:1 Mar 2013https://doi.org/10.1176/appi.pn.2013.3a23AbstractNew developments in neuroimaging and CSF studies of Alzheimer’s disease raise the question of what now constitutes the standard of care for the diagnostic workup for this condition. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have proposed new diagnostic criteria for mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) and dementia due to AD in which the disease is conceptualized along a spectrum from preclinical stages through MCI to dementia. Under the NIA/AA criteria, preclinical AD is diagnosed in individuals who are asymptomatic or subtly symptomatic and are “biomarker-positive.” Candidate biomarkers referenced in the criteria include the following:CSF assay of Aβ42 protein and tau proteinsVolumetric MRIFluorodeoxyglucose (FDG) PET imagingAmyloid PET imagingCSF assays of Aβ42, tau, and phosphorylated tau (P-tau) are already clinically available. They are used in specialty memory-disorder clinics and research settings to provide additional evidence for the differential diagnosis of AD. Volumetric MRI is also clinically available, but the standards for interpretation are not well established. FDG PET imaging has been available for years and is reimbursable for differentiating AD from other forms of dementia such as frontotemporal dementia.In recent months, a great deal of media attention has been paid to amyloid PET imaging, in which a ligand is used that binds to aggregated amyloid and deposited neuritic plaque. The pioneering work in this area was accomplished with Pittsburgh compound B (11C-PiB). Currently, three 18F-labeled molecules—florbetapir, florbetaben, and flutemetamol—are under active investigation. These compounds have the advantage over the 11C-labeled molecules in having a sufficiently long half-life that they can be express-shipped between states, making them more widely accessible. Both florbetapir and florbetaben have been approved by the FDA, and amyloid PET imaging became available for clinical use in 2012. From the FDA’s standpoint, one issue is whether adequate training has been provided to radiologists and other specialists in the proper interpretation of imaging data. The application for flutemetamol was accepted by the FDA in early January. The fact that amyloid is seen in the brains of cognitively normal individuals has raised some controversy; these compounds do not distinguish plaque from neuritic (pathological) plaque. Furthermore, it is not yet known whether normal individuals with plaque-positive scans will progress along the AD continuum over time. For these reasons, the best initial use of amyloid imaging will be to rule out AD as the disease process in a symptomatic individual with a negative scan. Also at issue is that neurofibrillary tangle burden has been found to be more predictive of cognitive impairment than plaque burden. At least one ligand now under investigation—18FDDNP—enables visualization of both plaque and tangles and of prion protein.As of this writing, these biomarkers are appropriately reserved for research settings. This is not to say that laboratory testing has no place in the diagnostic workup of dementia. The utility of routine laboratory evaluations to exclude reversible causes of cognitive impairment are well established. In addition, brain imaging (preferably MRI) is a standard component of the workup. In the early stages of disease, MRI or CT is often normal, but progressive atrophy is a helpful diagnostic finding.The NIA/AA criteria make no mention of ApoEε allele testing, an intentional omission. It is known that the ε4 allele is a risk factor for late-onset AD, while the ε2 allele is thought to confer some protection. APOEε testing may increase the specificity of diagnosis in a patient who meets clinical criteria for AD. In this case, the presence of the ε4/ε4 genotype increases the probability that AD is the correct diagnosis to about 97 percent. Nonetheless, ApoEε is a poor predictor of whether the disease will develop in an asymptomatic individual. ■Sandra Jacobson, M.D., is a research associate professor at the University of Arizona College of Medicine-Phoenix Banner Sun Health Research Institute. She is also the author of "Laboratory Medicine in Psychiatry and Behavioral Science" from American Psychiatric Publishing. APA members can order the book at a discount at http://www.appi.org/SearchCenter/Pages/SearchDetail.aspx?ItemId=62383. ISSUES NewArchived

The Johns Hopkins Atlas of Digital EEG: An Interactive Training Guide, 2nd Edition

Back to table of contents Previous article Next article Book ReviewFull AccessThe Johns Hopkins Atlas of Digital EEG: An Interactive Training Guide, 2nd EditionSandra Jacobson, M.D.Sandra JacobsonSearch for more papers by this author, M.D.Published Online:1 Jan 2012https://doi.org/10.1176/appi.neuropsych.12120112AboutSectionsView articleView PDFView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View articleEdited by KraussGregory L., M.D., FisherRobert S., M.D., Ph.D., and KaplanPeter W., MBBS, FRCP (London, UK) Baltimore, MD, The Johns Hopkins University Press, 2011 438 pages ISBN-13: 978-0801897337 $150.00With this second edition of a work already considered the standard textbook in digital EEG (d/EEG), these three noted epileptologists, Krauss, Fisher, and now Kaplan, have created a work that will become a classic in its field.Building on the strengths of the first edition, the authors have continued the tradition of including clearly reproduced tracings, accompanied by concise and clear labeling and interpretation, along with a brief and well-organized discussion of electrophysiology. The textbook also includes a d/EEG reading program on DVD-ROM, which allows the user to view EEG patterns in digital form and to change the format for better viewing; it offers a narrated discussion about selected patterns and waveforms, and enables the reader to view ictal EEG activity in tandem with video recordings on the same patient. There is no better way to help students get a “feel” for d/EEG patterns in relation to clinical manifestations of disease.The last section of the Atlas includes a series of three-dimensional brain reconstructions based on MRI images, showing EEG electrode positions and their relationship to underlying cortex. This is a big improvement over the older projections made onto skull radiographs. This section may be of particular interest to researchers considering the use of d/EEG in the study of various aspects of cognition. The multimedia nature of this work renders what can be a very dull subject interesting. One could envision the use of these materials for individual study at a workstation, or for a group at EEG reading rounds, or even in a lecture setting.The content is certainly comprehensive enough for the beginning electroencephalographer, and, with the augmentation of pediatric d/EEG material, gets closer to the encyclopedic sort of reference needed for everyday work in the d/EEG laboratory. Would it be too much to expect, with this quality of resource available, that students in neuropsychiatry and neurology would, in the course of training, develop a basic understanding of and appreciation for d/EEG, regardless of specialty? The authors have done their part—have, in fact, raised the bar for d/EEG training and education by providing this excellent program. It remains for training directors and other educators to take up the charge.Dr. Jacobson is Research Associate Professor. University of Arizona College of Medicine–Phoenix, and is affiliated with the Banner Sun Health Research Institute. FiguresReferencesCited byDetailsCited ByNone Volume 24Issue 1 Winter 2012Pages 115-115 Metrics History Published online 1 January 2012 Published in print 1 January 2012

Neuropathological findings of PSP in the elderly without clinical PSP: Possible incidental PSP?

Aims We aimed to describe cases with incidental neuropathological findings of progressive supranuclear palsy (PSP) from the Banner Sun Health Research Institute Brain and Body Donation Program. Methods We performed a retrospective review of 277 subjects with longitudinal motor and neuropsychological assessments who came to autopsy. The mean Gallyas-positive PSP features grading for subjects with possible incidental neuropathological PSP was compared to those of subjects with clinically manifest disease. Results There were 5 cases with histopathological findings suggestive of PSP, but no parkinsonism, dementia or movement disorder during life. Cognitive evaluation revealed 4 of the 5 cases to be cognitively normal; one case had amnestic mild cognitive impairment (MCI) in her last year of life. The mean age at death of the 5 cases was 88.9 years (range 80–94). All 5 individuals had histopathologic microscopic findings suggestive of PSP. Mean Gallyas-positive PSP features grading was significantly lower in subjects with possible incidental neuropathological PSP than subjects with clinical PSP, particularly in the subthalamic nucleus. Conclusions We present 5 patients with histopathological findings suggestive of PSP, without clinical PSP, dementia or parkinsonism during life. These incidental neuropathological PSP findings may represent the early or pre-symptomatic stage of PSP. The mean Gallyas-positive PSP features grading was significantly lower in possible incidental PSP than in clinical PSP, thus suggesting that a threshold of pathological burden needs to be reached within the typically affected areas in PSP before clinical signs and symptoms appear.

2010 Wasn't Good Year on Alzheimer's Front

2010 Wasn't Good Year on Alzheimer's Front

Postmortem interval effect on RNA and gene expression in human brain tissue

Banked tissue is essential to the study of neurological disease but using postmortem tissue introduces a number of possible confounds. Foremost amongst these are factors relating to variation in postmortem interval (PMI). Currently there are conflicting reports on how PMI affects overall RNA integrity, and very few reports of how gene expression is affected by PMI. We analyzed total RNA extracted from frozen cerebellar cortex from 79 deceased human subjects enrolled in the Banner Sun Health Research Institute Brain and Body Donation Program. The PMI, which ranged from 1.5 to 45h, correlated with overall RNA quality measures including RNA Integrity Number (RIN) (r=-0.34, P=0.002) and RNA quantitative yield (r=-0.25, P=0.02). Additionally, we determined the expression of 89 genes using a PCR-based gene expression array (RT(2) Profiler™ PCR Array: Human Alzheimer's Disease; SABiosciences™, Frederick, MD). A greater proportion of genes had decreased rather than increased expression with increasing PMI (65/89 vs. 20/89; P<0.0001). Of these, transcripts from the genes ADAM9, LPL, PRKCG, and SERPINA3 had significantly decreased expression with increasing PMI (P<0.01). No individual gene transcripts had significantly increased expression with increasing PMI. In conclusion, it is apparent that RNA degrades progressively with increasing PMI and that measurement of gene expression in brain tissue with longer PMI may give artificially low values. For tissue derived from autopsy, a short PMI optimizes its utility for molecular research.

Commentary on “Design of comprehensive Alzheimer's disease centers to address unmet national needs”

Alzheimer's & DementiaVolume 6, Issue 2 p. 156-157 Meeting Report Commentary on “Design of comprehensive Alzheimer's disease centers to address unmet national needs” Marwan N. Sabbagh, Corresponding Author Marwan N. Sabbagh [email protected] 623-875-6500 | Fax: 623-875-6504 The Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute, Sun City, AZ, USA Corresponding author. Tel.: 623-875-6500; Fax: 623-875-6504. E-mail address: [email protected]Search for more papers by this author Marwan N. Sabbagh, Corresponding Author Marwan N. Sabbagh [email protected] 623-875-6500 | Fax: 623-875-6504 The Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute, Sun City, AZ, USA Corresponding author. Tel.: 623-875-6500; Fax: 623-875-6504. E-mail address: [email protected]Search for more papers by this author First published: 01 March 2010 https://doi.org/10.1016/j.jalz.2010.01.006Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume6, Issue2March 2010Pages 156-157 RelatedInformation

On Cholesterol Levels and Statins in Cognitive Decline and Alzheimer Disease

The Cleo Roberts Center, Sun Health Research Institute, Sun City, AZ Supported by AG 019610 and the Sun Health Research Institute. Dr Sabbagh receives grant funding from Pfizer, Eisai, Novartis, GSK, Elan, Wyeth, Medivation, and Abbott. Dr Sabbagh is a consultant to Eli Lilly, Wyeth and Amerisciences. Reprints: Marwan N. Sabbagh, MD, FAAN, The Cleo Roberts Center, Banner Sun Health Research Institute, 10515 W. Santa Fe Dr, Sun City, AZ 85351 (e-mail: [email protected]).